A framework for the correction of slow physiological drifts during MR-guided HIFU therapies: Proof of concept

Energy Technology Data Exchange (ETDEWEB)

Zachiu, Cornel, E-mail: C.Zachiu@umcutrecht.nl; Moonen, Chrit; Ries, Mario [Imaging Division, UMC Utrecht, Heidelberglaan 100, Utrecht 3584 CX (Netherlands); Denis de Senneville, Baudouin [Imaging Division, UMC Utrecht, Heidelberglaan 100, Utrecht 3584 CX (Netherlands); Mathematical Institute of Bordeaux, University of Bordeaux, Talence Cedex 33405 (France)

2015-07-15

Purpose: While respiratory motion compensation for magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During lengthy interventions, the magnitude of the latter can exceed acceptable therapeutic margins. The goal of the present study is to exploit the episodic workflow of these therapies to implement a motion correction strategy for slow varying drifts of the target area and organs at risk over the entire duration of the intervention. Methods: The therapeutic workflow of a MR-guided HIFU intervention is in practice often episodic: Bursts of energy delivery are interleaved with periods of inactivity, allowing the effects of the beam on healthy tissues to recede and/or during which the plan of the intervention is reoptimized. These periods usually last for at least several minutes. It is at this time scale that organ drifts due to slow physiological motion become significant. In order to capture these drifts, the authors propose the integration of 3D MR scans in the therapy workflow during the inactivity intervals. Displacements were estimated using an optical flow algorithm applied on the 3D acquired images. A preliminary study was conducted on ten healthy volunteers. For each volunteer, 3D MR images of the abdomen were acquired at regular intervals of 10 min over a total duration of 80 min. Motion analysis was restricted to the liver and kidneys. For validating the compatibility of the proposed motion correction strategy with the workflow of a MR-guided HIFU therapy, an in vivo experiment on a porcine liver was conducted. A volumetric HIFU ablation was completed over a time span of 2 h. A 3D image was acquired before the first sonication, as well as after each sonication. Results: Following the volunteer study, drifts larger than 8 mm for the liver and 5 mm for the kidneys prove that

High-Intensity Focused Ultrasound (HIFU) in Localized Prostate Cancer Treatment

International Nuclear Information System (INIS)

Alkhorayef, Mohammed; Mahmoud, Mustafa Z.; Alzimami, Khalid S.; Sulieman, Abdelmoneim; Fagiri, Maram A.

2015-01-01

High-intensity focused ultrasound (HIFU) applies high-intensity focused ultrasound energy to locally heat and destroy diseased or damaged tissue through ablation. This study intended to review HIFU to explain the fundamentals of HIFU, evaluate the evidence concerning the role of HIFU in the treatment of prostate cancer (PC), review the technologies used to perform HIFU and the published clinical literature regarding the procedure as a primary treatment for PC. Studies addressing HIFU in localized PC were identified in a search of internet scientific databases. The analysis of outcomes was limited to journal articles written in English and published between 2000 and 2013. HIFU is a non-invasive approach that uses a precisely delivered ultrasound energy to achieve tumor cell necrosis without radiation or surgical excision. In current urological oncology, HIFU is used clinically in the treatment of PC. Clinical research on HIFU therapy for localized PC began in the 1990s, and the majority of PC patients were treated with the Ablatherm device. HIFU treatment for localized PC can be considered as an alternative minimally invasive therapeutic modality for patients who are not candidates for radical prostatectomy. Patients with lower pre-HIFU PSA level and favourable pathologic Gleason score seem to present better oncologic outcomes. Future advances in technology and safety will undoubtedly expand the HIFU role in this indication as more of patient series are published, with a longer follow-up period

HematoPorphyrin Monomethyl Ether polymer contrast agent for ultrasound/photoacoustic dual-modality imaging-guided synergistic high intensity focused ultrasound (HIFU) therapy.

Science.gov (United States)

Yan, Sijing; Lu, Min; Ding, Xiaoya; Chen, Fei; He, Xuemei; Xu, Chunyan; Zhou, Hang; Wang, Qi; Hao, Lan; Zou, Jianzhong

2016-08-18

This study is to prepare a hematoporphyrin monomethyl ether (HMME)-loaded poly(lactic-co-glycolic acid) (PLGA) microcapsules (HMME/PLGA), which could not only function as efficient contrast agent for ultrasound (US)/photoacoustic (PA) imaging, but also as a synergistic agent for high intensity focused ultrasound (HIFU) ablation. Sonosensitizer HMME nanoparticles were integrated into PLGA microcapsules with the double emulsion evaporation method. After characterization, the cell-killing and cell proliferation-inhibiting effects of HMME/PLGA microcapsules on ovarian cancer SKOV3 cells were assessed. The US/PA imaging-enhancing effects and synergistic effects on HIFU were evaluated both in vitro and in vivo. HMME/PLGA microcapsules were highly dispersed with well-defined spherical morphology (357 ± 0.72 nm in diameter, PDI = 0.932). Encapsulation efficiency and drug-loading efficiency were 58.33 ± 0.95% and 4.73 ± 0.15%, respectively. The HMME/PLGA microcapsules remarkably killed the SKOV3 cells and inhibited the cell proliferation, significantly enhanced the US/PA imaging results and greatly enhanced the HIFU ablation effects on ovarian cancer in nude mice by the HMME-mediated sono-dynamic chemistry therapy (SDT). HMME/PLGA microcapsules represent a potential multifunctional contrast agent for HIFU diagnosis and treatment, which might provide a novel strategy for the highly efficient imaging-guided non-invasive HIFU synergistic therapy for cancers by SDT in clinic.

CT and Ultrasound Guided Stereotactic High Intensity Focused Ultrasound (HIFU)

Science.gov (United States)

Wood, Bradford J.; Yanof, J.; Frenkel, V.; Viswanathan, A.; Dromi, S.; Oh, K.; Kruecker, J.; Bauer, C.; Seip, R.; Kam, A.; Li, K. C. P.

2006-05-01

To demonstrate the feasibility of CT and B-mode Ultrasound (US) targeted HIFU, a prototype coaxial focused ultrasound transducer was registered and integrated to a CT scanner. CT and diagnostic ultrasound were used for HIFU targeting and monitoring, with the goals of both thermal ablation and non-thermal enhanced drug delivery. A 1 megahertz coaxial ultrasound transducer was custom fabricated and attached to a passive position-sensing arm and an active six degree-of-freedom robotic arm via a CT stereotactic frame. The outer therapeutic transducer with a 10 cm fixed focal zone was coaxially mounted to an inner diagnostic US transducer (2-4 megahertz, Philips Medical Systems). This coaxial US transducer was connected to a modified commercial focused ultrasound generator (Focus Surgery, Indianapolis, IN) with a maximum total acoustic power of 100 watts. This pre-clinical paradigm was tested for ability to heat tissue in phantoms with monitoring and navigation from CT and live US. The feasibility of navigation via image fusion of CT with other modalities such as PET and MRI was demonstrated. Heated water phantoms were tested for correlation between CT numbers and temperature (for ablation monitoring). The prototype transducer and integrated CT/US imaging system enabled simultaneous multimodality imaging and therapy. Pre-clinical phantom models validated the treatment paradigm and demonstrated integrated multimodality guidance and treatment monitoring. Temperature changes during phantom cooling corresponded to CT number changes. Contrast enhanced or non-enhanced CT numbers may potentially be used to monitor thermal ablation with HIFU. Integrated CT, diagnostic US, and therapeutic focused ultrasound bridges a gap between diagnosis and therapy. Preliminary results show that the multimodality system may represent a relatively inexpensive, accessible, and simple method of both targeting and monitoring HIFU effects. Small animal pre-clinical models may be translated to large

High speed observation of HIFU-induced cavitation cloud near curved rigid boundaries

International Nuclear Information System (INIS)

Zuo, Z G; Wang, F B; Liu, S H; Wu, S J

2015-01-01

This paper focuses on the experimental study of the influence of surface curvature to the behaviour of HIFU-induced cavitation cloud. A Q-switched ruby pulse laser is used to induce cavitation nuclei in deionized water. A piezoelectric ultrasonic transducer (1.7 MHz) provides a focused ultrasound field to inspire the nucleus to cavitation cloud. A PZT probe type hydrophone is applied for measuring the HIFU sound field. It was observed that the motion of cavitation cloud located near the boundary is significantly influenced by the distance between cloud and boundary, as well as the curvature of the boundary. The curvature was defined by parameters λ and ξ. Convex boundary, concave boundary, and flat boundary correspond to ξ <1, ξ >1 and ξ = 1, respectively. Different behaviours of the cloud, including the migration of the cloud, the characteristics of oscillation, etc., were observed under different boundary curvatures by high-speed photography. Sonoluminescence of the acoustic cavitation bubble clouds were also studied to illustrate the characteristics of acoustic streaming

Image Guidance and Assessment of Radiation Induced Gene Therapy

National Research Council Canada - National Science Library

Pelizzari, Charles

2004-01-01

Image guidance and assessment techniques are being developed for combined radiation/gene therapy, which utilizes a radiation-inducible gene promoter to cause expression of tumor necrosis factor alpha...

TU-A-210-01: HIFU Physics and Delivery

Energy Technology Data Exchange (ETDEWEB)

Eames, M. [Focused Ultrasound Foundation (United States)

2015-06-15

High-intensity focused ultrasound (HIFU) has developed rapidly in recent years and is used frequently for clinical treatments in Asia and Europe with increasing clinical use and clinical trial activity in the US, making it an important medical technology with which the medical physics community must become familiar. Akin to medical devices that deliver treatments using ionizing radiation, HIFU relies on emitter geometry to non-invasively form a tight focus that can be used to affect diseased tissue while leaving healthy tissue intact. HIFU is unique in that it does not involve the use of ionizing radiation, it causes thermal necrosis in 100% of the treated tissue volume, and it has an immediate treatment effect. However, because it is an application of ultrasound energy, HIFU interacts strongly with tissue interfaces, which makes treatment planning challenging. In order to appreciate the advantages and disadvantages of HIFU as a thermal therapy, it is important to understand the underlying physics of ultrasound tissue interactions. The first lecture in the session will provide an overview of the physics of ultrasound wave propagation; the mechanism for the accumulation of heat in soft-tissue; image-guidance modalities including temperature monitoring; current clinical applications and commercial devices; active clinical trials; alternate mechanisms of action (future of FUS). The second part of the session will compare HIFU to existing ionization radiation techniques. The difficulties in defining a clear concept of absorbed dose for HIFU will be discussed. Some of the technical challenges that HIFU faces will be described, with an emphasis on how the experience of radiation oncology physicists could benefit the field. Learning Objectives: Describe the basic physics and biology of HIFU, including treatment delivery and image guidance techniques. Summarize existing and emerging clinical applications and manufacturers for HIFU. Understand that thermal ablation with

TU-A-210-01: HIFU Physics and Delivery

International Nuclear Information System (INIS)

Eames, M.

2015-01-01

High-intensity focused ultrasound (HIFU) has developed rapidly in recent years and is used frequently for clinical treatments in Asia and Europe with increasing clinical use and clinical trial activity in the US, making it an important medical technology with which the medical physics community must become familiar. Akin to medical devices that deliver treatments using ionizing radiation, HIFU relies on emitter geometry to non-invasively form a tight focus that can be used to affect diseased tissue while leaving healthy tissue intact. HIFU is unique in that it does not involve the use of ionizing radiation, it causes thermal necrosis in 100% of the treated tissue volume, and it has an immediate treatment effect. However, because it is an application of ultrasound energy, HIFU interacts strongly with tissue interfaces, which makes treatment planning challenging. In order to appreciate the advantages and disadvantages of HIFU as a thermal therapy, it is important to understand the underlying physics of ultrasound tissue interactions. The first lecture in the session will provide an overview of the physics of ultrasound wave propagation; the mechanism for the accumulation of heat in soft-tissue; image-guidance modalities including temperature monitoring; current clinical applications and commercial devices; active clinical trials; alternate mechanisms of action (future of FUS). The second part of the session will compare HIFU to existing ionization radiation techniques. The difficulties in defining a clear concept of absorbed dose for HIFU will be discussed. Some of the technical challenges that HIFU faces will be described, with an emphasis on how the experience of radiation oncology physicists could benefit the field. Learning Objectives: Describe the basic physics and biology of HIFU, including treatment delivery and image guidance techniques. Summarize existing and emerging clinical applications and manufacturers for HIFU. Understand that thermal ablation with

Non-invasive treatment efficacy evaluation for high-intensity focused ultrasound therapy using magnetically induced magnetoacoustic measurement

Science.gov (United States)

Guo, Gepu; Wang, Jiawei; Ma, Qingyu; Tu, Juan; Zhang, Dong

2018-04-01

Although the application of high intensity focused ultrasound (HIFU) has been demonstrated to be a non-invasive treatment technology for tumor therapy, the real-time temperature monitoring is still a key issue in the practical application. Based on the temperature-impedance relation, a fixed-point magnetically induced magnetoacoustic measurement technology of treatment efficacy evaluation for tissue thermocoagulation during HIFU therapy is developed with a sensitive indicator of critical temperature monitoring in this study. With the acoustic excitation of a focused transducer in the magnetoacoustic tomography with the magnetic induction system, the distributions of acoustic pressure, temperature, electrical conductivity, and acoustic source strength in the focal region are simulated, and the treatment time dependences of the peak amplitude and the corresponding amplitude derivative under various acoustic powers are also achieved. It is proved that the strength peak of acoustic sources is generated by tissue thermocoagulation with a sharp conductivity variation. The peak amplitude of the transducer collected magnetoacoustic signal increases accordingly along with the increase in the treatment time under a fixed acoustic power. When the temperature in the range with the radial and axial widths of about ±0.46 mm and ±2.2 mm reaches 69 °C, an obvious peak of the amplitude derivative can be achieved and used as a sensitive indicator of the critical status of treatment efficacy. The favorable results prove the feasibility of real-time non-invasive temperature monitoring and treatment efficacy evaluation for HIFU ablation using the magnetically induced magnetoacoustic measurement, and might provide a new strategy for accurate dose control during HIFU therapy.

TU-B-210-01: MRg HIFU - Bone and Soft Tissue Tumor Ablation

International Nuclear Information System (INIS)

Ghanouni, P.

2015-01-01

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advanced techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips

TU-B-210-02: MRg HIFU - Advanced Approaches for Ablation and Hyperthermia

Energy Technology Data Exchange (ETDEWEB)

Moonen, C. [University Medical Center Utrecht (Netherlands)

2015-06-15

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advanced techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.

TU-B-210-01: MRg HIFU - Bone and Soft Tissue Tumor Ablation

Energy Technology Data Exchange (ETDEWEB)

Ghanouni, P. [Stanford University (United States)

2015-06-15

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advanced techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.

Cranial nerve threshold for thermal injury induced by MRI-guided high-intensity focused ultrasound (MRgHIFU): preliminary results on an optic nerve model.

Science.gov (United States)

Harnof, Sagi; Zibly, Zion; Cohen, Zvi; Shaw, Andrew; Schlaff, Cody; Kassel, Neal F

2013-04-01

Future clinical applications of magnetic resonance imaging-guided high-intensity focused ultrasound (MRgHIFU) are moving toward the management of different intracranial pathologies. We sought to validate the production, safety, and efficacy of thermal injury to cranial nerves generated by MRgHIFU. In this study, five female domestic pigs underwent a standard bifrontal craniectomy under general anesthesia. Treatment was then given using an MRgHIFU system to induce hyperthermic ablative sonication (6 to 10 s; 50 to 2000 J.) Histological analyses were done to confirm nerve damage; temperature measured on the optic nerve was approximately 53.4°C (range: 39°C to 70°C.) Histology demonstrated a clear definition between a necrotic, transitional zone, and normal tissue. MRgHIFU induces targeted thermal injury to nervous tissue within a specific threshold of 50°C to 60°C with the tissue near the sonication center yielding the greatest effect; adjacent tissue showed minimal changes. Additional studies utilizing this technology are required to further establish accurate threshold parameters for optic nerve thermo-ablation.

Segmental liver resection assisted by HIFU: tissue precauterization using a toroidal-shaped HIFU transducer

Science.gov (United States)

N'Djin, W. A.; Melodelima, D.; Schenone, F.; Rivoire, M.; Chapelon, J. Y.

2010-03-01

The development of new cauterization techniques for hepatic resection is critical for improving the safety of the procedure. Previous studies showed the feasibility of using HIFU or radiofrequency precoagulation to limit blood loss during dissection of the organ. Here we report a new therapeutic modality using high intensity focused ultrasound (HIFU) to perform a bloodless hepatic resection that could represent a promising alternative. A comparative study was performed to evaluate the interest of using this complementary tool to improve surgical resection in the liver. This study used a 3 MHz HIFU toroidal-shaped phased array transducer which allows the generation of a single conical lesion of 7 cm3 in 40 seconds. In order to minimize blood loss and dissection time, a barrier of coagulative necrosis was generated with the HIFU device before hepatectomy, by juxtaposing single conical lesions on the line of dissection. Resection assisted by HIFU (RA-HIFU) was compared with classical dissections with clamping (RC) and without clamping (Control). For each technique 14 partial liver resections were performed in seven pigs. The parameters examined were vascular control and times of treatment. Precoagulation allowed the vascular isolation of small vessels and surgical clips were mainly used for the control of vessels>5 mm in diameter. The number of clips used per unit of liver surface dissected in RA-HIFU (0.8±0.3 cm-2) was significantly lower than in the other groups (RC: 1.6±0.4 cm-2, Control: 1.8±0.8 cm-2, p<0.01). In addition, blood loss was lower in RA-HIFU (7.4±6.5 ml.cm-2) than in RC (11.2±4.5 ml.cm-2) and Control (14.0±6.7 ml.cm-2). The time of dissection in RA-HIFU (13±5 min) was shorter than in RC (23±8 minutes) and Control (18±5 minutes). The feasibility and the efficiency of RA-HIFU using a toroidal-shaped HIFU transducer without additional devices were demonstrated. This technique enhances the resection procedure and will be able to be tested in

Salvage HIFU after radiotherapy and salvage radiotherapy after HIFU in locally recurrent prostate cancer: Retrospective analysis of morbidity

International Nuclear Information System (INIS)

Lee, J.-W.; Hannoun-Leviac, J.-M.; Chevallier, D.; Rouscoff, Y.; Durand, M.; Amiel, J.; Gal, J.; Natale, R.; Chand, M.-E.; Raffaelli, C.; Ambrosetti, D.

2012-01-01

To evaluate the toxicity of therapeutic sequences High Intensity Focused Ultrasound (HIFU)-salvage radiotherapy (HIFU-RT) or radiotherapy-salvage HIFU (RT-HIFU) in case of locally recurrent prostate cancer. Nineteen patients had a local recurrence of prostate cancer. Among them, 10 patients were treated by HIFU-RT and 9 patients by RT- HIFU (4 by external beam radiotherapy [EBR] and 5 by brachytherapy [BRACHY]). Urinary side effects were assessed using CTCAE v4. At the time of the initial management, the median age was 66.5 years (53 72), the median PSA was 10.8 ng/mL (3.4 50) and the median initial Gleason score was 6.3 (5 8). Median follow-up after salvage treatment was 46.3 months (2 108). Thirty percent of the patients in the HIFU-RT group and 33.3 % of the patients in the RT-HIFU group, all belonging to the sub-group BRACHY-HIFU, had urinary complication greater than or equal to grade 2. Among all the patients, only 1 had grade 1 gastrointestinal toxicity. BRACHY-HIFU sequence seems to be purveyor of many significant urinary side effects. A larger database is needed to confirm this conclusion. (authors)

PASSIVE CAVITATION DETECTION DURING PULSED HIFU EXPOSURES OF EX VIVO TISSUES AND IN VIVO MOUSE PANCREATIC TUMORS

OpenAIRE

Li, Tong; Chen, Hong; Khokhlova, Tatiana; Wang, Yak-Nam; Kreider, Wayne; He, Xuemei; Hwang, Joo Ha

2014-01-01

Pulsed high-intensity focused ultrasound (pHIFU) has been demonstrated to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitatio...

Monitoring and guidance of HIFU beams with dual-mode ultrasound arrays.

Science.gov (United States)

Ballard, John R; Casper, Andrew J; Ebbini, Emad S

2009-01-01

We present experimental results illustrating the unique advantages of dual-mode array (DMUA) systems in monitoring and guidance of high intensity focused ultrasound (HIFU) lesion formation. DMUAs offer a unique paradigm in image-guided surgery; one in which images obtained using the same therapeutic transducer provide feedback for: 1) refocusing the array in the presence of strongly scattering objects, e.g. the ribs, 2) temperature change at the intended location of the HIFU focus, and 3) changes in the echogenicity of the tissue in response to therapeutic HIFU. These forms of feedback have been demonstrated in vitro in preparation for the design and implementation of a real-time system for imaging and therapy with DMUAs. The results clearly demonstrate that DMUA image feedback is spatially accurate and provide sufficient spatial and contrast resolution for identification of high contrast objects like the ribs and significant blood vessels in the path of the HIFU beam.

Study of a scanning HIFU therapy protocol, Part II: Experiment and results

Science.gov (United States)

Andrew, Marilee A.; Kaczkowski, Peter; Cunitz, Bryan W.; Brayman, Andrew A.; Kargl, Steven G.

2003-04-01

Instrumentation and protocols for creating scanned HIFU lesions in freshly excised bovine liver were developed in order to study the in vitro HIFU dose response and validate models. Computer-control of the HIFU transducer and 3-axis positioning system provided precise spatial placement of the thermal lesions. Scan speeds were selected in the range of 1 to 8 mm/s, and the applied electrical power was varied from 20 to 60 W. These parameters were chosen to hold the thermal dose constant. A total of six valid scans of 15 mm length were created in each sample; a 3.5 MHz single-element, spherically focused transducer was used. Treated samples were frozen, then sliced in 1.27 mm increments. Digital photographs of slices were downloaded to computer for image processing and analysis. Lesion characteristics, including the depth within the tissue, axial length, and radial width, were computed. Results were compared with those generated from modified KZK and BHTE models, and include a comparison of the statistical variation in the across-scan lesion radial width. [Work supported by USAMRMC.

Impact of cavitation on lesion formation induced by high intensity focused ultrasound

International Nuclear Information System (INIS)

Fan Pengfei; Jie Yu; Yang Xin; Tu Juan; Guo Xiasheng; Zhang Dong; Huang Pintong

2017-01-01

High intensity focused ultrasound (HIFU) has shown a great promise in noninvasive cancer therapy. The impact of acoustic cavitation on the lesion formation induced by HIFU is investigated both experimentally and theoretically in transparent protein-containing gel and ex vivo liver tissue samples. A numerical model that accounts for nonlinear acoustic propagation and heat transfer is used to simulate the lesion formation induced by the thermal effect. The results showed that lesions could be induced in the samples exposed to HIFU with various acoustic pressures and pulse lengths. The measured areas of lesions formed in the lateral direction were comparable to the simulated results, while much larger discrepancy was observed between the experimental and simulated data for the areas of longitudinal lesion cross-section. Meanwhile, a series of stripe-wiped-off B-mode pictures were obtained by using a special imaging processing method so that HIFU-induced cavitation bubble activities could be monitored in real-time and quantitatively analyzed as the functions of acoustic pressure and pulse length. The results indicated that, unlike the lateral area of HIFU-induced lesion that was less affected by the cavitation activity, the longitudinal cross-section of HIFU-induced lesion was significantly influenced by the generation of cavitation bubbles through the temperature elevation resulting from HIFU exposures. Therefore, considering the clinical safety in HIFU treatments, more attention should be paid on the lesion formation in the longitudinal direction to avoid uncontrollable variation resulting from HIFU-induced cavitation activity. (paper)

[Focused ultrasound therapy: current status and potential applications in neurosurgery].

Science.gov (United States)

Dervishi, E; Aubry, J-F; Delattre, J-Y; Boch, A-L

2013-12-01

High Intensity Focused Ultrasound (HIFU) therapy is an innovative approach for tissue ablation, based on high intensity focused ultrasound beams. At the focus, HIFU induces a temperature elevation and the tissue can be thermally destroyed. In fact, this approach has been tested in a number of clinical studies for the treatment of several tumors, primarily the prostate, uterine, breast, bone, liver, kidney and pancreas. For transcranial brain therapy, the skull bone is a major limitation, however, new adaptive techniques of phase correction for focusing ultrasound through the skull have recently been implemented by research systems, paving the way for HIFU therapy to become an interesting alternative to brain surgery and radiotherapy. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

TU-A-210-02: HIFU: Why Should a Radiation Oncology Physicist Pay Attention?

International Nuclear Information System (INIS)

Schlesinger, D.

2015-01-01

High-intensity focused ultrasound (HIFU) has developed rapidly in recent years and is used frequently for clinical treatments in Asia and Europe with increasing clinical use and clinical trial activity in the US, making it an important medical technology with which the medical physics community must become familiar. Akin to medical devices that deliver treatments using ionizing radiation, HIFU relies on emitter geometry to non-invasively form a tight focus that can be used to affect diseased tissue while leaving healthy tissue intact. HIFU is unique in that it does not involve the use of ionizing radiation, it causes thermal necrosis in 100% of the treated tissue volume, and it has an immediate treatment effect. However, because it is an application of ultrasound energy, HIFU interacts strongly with tissue interfaces, which makes treatment planning challenging. In order to appreciate the advantages and disadvantages of HIFU as a thermal therapy, it is important to understand the underlying physics of ultrasound tissue interactions. The first lecture in the session will provide an overview of the physics of ultrasound wave propagation; the mechanism for the accumulation of heat in soft-tissue; image-guidance modalities including temperature monitoring; current clinical applications and commercial devices; active clinical trials; alternate mechanisms of action (future of FUS). The second part of the session will compare HIFU to existing ionization radiation techniques. The difficulties in defining a clear concept of absorbed dose for HIFU will be discussed. Some of the technical challenges that HIFU faces will be described, with an emphasis on how the experience of radiation oncology physicists could benefit the field. Learning Objectives: Describe the basic physics and biology of HIFU, including treatment delivery and image guidance techniques. Summarize existing and emerging clinical applications and manufacturers for HIFU. Understand that thermal ablation with

TU-A-210-02: HIFU: Why Should a Radiation Oncology Physicist Pay Attention?

Energy Technology Data Exchange (ETDEWEB)

Schlesinger, D. [University of Virginia Health Systems (United States)

2015-06-15

High-intensity focused ultrasound (HIFU) has developed rapidly in recent years and is used frequently for clinical treatments in Asia and Europe with increasing clinical use and clinical trial activity in the US, making it an important medical technology with which the medical physics community must become familiar. Akin to medical devices that deliver treatments using ionizing radiation, HIFU relies on emitter geometry to non-invasively form a tight focus that can be used to affect diseased tissue while leaving healthy tissue intact. HIFU is unique in that it does not involve the use of ionizing radiation, it causes thermal necrosis in 100% of the treated tissue volume, and it has an immediate treatment effect. However, because it is an application of ultrasound energy, HIFU interacts strongly with tissue interfaces, which makes treatment planning challenging. In order to appreciate the advantages and disadvantages of HIFU as a thermal therapy, it is important to understand the underlying physics of ultrasound tissue interactions. The first lecture in the session will provide an overview of the physics of ultrasound wave propagation; the mechanism for the accumulation of heat in soft-tissue; image-guidance modalities including temperature monitoring; current clinical applications and commercial devices; active clinical trials; alternate mechanisms of action (future of FUS). The second part of the session will compare HIFU to existing ionization radiation techniques. The difficulties in defining a clear concept of absorbed dose for HIFU will be discussed. Some of the technical challenges that HIFU faces will be described, with an emphasis on how the experience of radiation oncology physicists could benefit the field. Learning Objectives: Describe the basic physics and biology of HIFU, including treatment delivery and image guidance techniques. Summarize existing and emerging clinical applications and manufacturers for HIFU. Understand that thermal ablation with

High intensity focused ultrasound (HIFU) applied to hepato-bilio-pancreatic and the digestive system—current state of the art and future perspectives

Science.gov (United States)

Diana, Michele; Schiraldi, Luigi; Liu, Yu-Yin; Memeo, Riccardo; Mutter, Didier; Pessaux, Patrick

2016-01-01

Background High intensity focused ultrasound (HIFU) is emerging as a valid minimally-invasive image-guided treatment of malignancies. We aimed to review to current state of the art of HIFU therapy applied to the digestive system and discuss some promising avenues of the technology. Methods Pertinent studies were identified through PubMed and Embase search engines using the following keywords, combined in different ways: HIFU, esophagus, stomach, liver, pancreas, gallbladder, colon, rectum, and cancer. Experimental proof of the concept of endoluminal HIFU mucosa/submucosa ablation using a custom-made transducer has been obtained in vivo in the porcine model. Results Forty-four studies reported on the clinical use of HIFU to treat liver lesions, while 19 series were found on HIFU treatment of pancreatic cancers and four studies included patients suffering from both liver and pancreatic cancers, reporting on a total of 1,682 and 823 cases for liver and pancreas, respectively. Only very limited comparative prospective studies have been reported. Conclusions Digestive system clinical applications of HIFU are limited to pancreatic and liver cancer. It is safe and well tolerated. The exact place in the hepatocellular carcinoma (HCC) management algorithm remains to be defined. HIFU seems to add clear survival advantages over trans arterial chemo embolization (TACE) alone and similar results when compared to radio frequency (RF). For pancreatic cancer, HIFU achieves consistent cancer-related pain relief. Further research is warranted to improve targeting accuracy and efficacy monitoring. Furthermore, additional work is required to transfer this technology on appealing treatments such as endoscopic HIFU-based therapies. PMID:27500145

Robust adaptive extended Kalman filtering for real time MR-thermometry guided HIFU interventions.

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Roujol, Sébastien; de Senneville, Baudouin Denis; Hey, Silke; Moonen, Chrit; Ries, Mario

2012-03-01

Real time magnetic resonance (MR) thermometry is gaining clinical importance for monitoring and guiding high intensity focused ultrasound (HIFU) ablations of tumorous tissue. The temperature information can be employed to adjust the position and the power of the HIFU system in real time and to determine the therapy endpoint. The requirement to resolve both physiological motion of mobile organs and the rapid temperature variations induced by state-of-the-art high-power HIFU systems require fast MRI-acquisition schemes, which are generally hampered by low signal-to-noise ratios (SNRs). This directly limits the precision of real time MR-thermometry and thus in many cases the feasibility of sophisticated control algorithms. To overcome these limitations, temporal filtering of the temperature has been suggested in the past, which has generally an adverse impact on the accuracy and latency of the filtered data. Here, we propose a novel filter that aims to improve the precision of MR-thermometry while monitoring and adapting its impact on the accuracy. For this, an adaptive extended Kalman filter using a model describing the heat transfer for acoustic heating in biological tissues was employed together with an additional outlier rejection to address the problem of sparse artifacted temperature points. The filter was compared to an efficient matched FIR filter and outperformed the latter in all tested cases. The filter was first evaluated on simulated data and provided in the worst case (with an approximate configuration of the model) a substantial improvement of the accuracy by a factor 3 and 15 during heat up and cool down periods, respectively. The robustness of the filter was then evaluated during HIFU experiments on a phantom and in vivo in porcine kidney. The presence of strong temperature artifacts did not affect the thermal dose measurement using our filter whereas a high measurement variation of 70% was observed with the FIR filter.

Molecular targeting of gene therapy and radiotherapy

International Nuclear Information System (INIS)

Weichselbaum, R.R.; Kufe, D.W.; Advani, S.J.; Roizman, B.

2001-01-01

The full promise of gene therapy has been limited by the lack of specificity of vectors for tumor tissue as well as the lack of antitumor efficacy of transgenes encoded by gene delivery systems. In this paper we review our studies investigating two modifications of gene therapy combined with radiotherapy. The first investigations described include studies of radiation inducible gene therapy. In this paradigm, radio-inducible DNA sequences from the CarG elements of the Egr-1 promoter are cloned upstream of a cDNA encoding TNFa. The therapeutic gene (TNFa) is induced by radiation within the tumor microenvironment. In the second paradigm, genetically engineered herpes simplex virus (HSV-1) is induced by ionizing radiation to proliferate within the tumor volume. These modifications of radiotherapy and gene therapy may enhance the efficacy of both treatments

Efficient and controllable thermal ablation induced by short-pulsed HIFU sequence assisted with perfluorohexane nanodroplets.

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Chang, Nan; Lu, Shukuan; Qin, Dui; Xu, Tianqi; Han, Meng; Wang, Supin; Wan, Mingxi

2018-07-01

A HIFU sequence with extremely short pulse duration and high pulse repetition frequency can achieve thermal ablation at a low acoustic power using inertial cavitation. Because of its cavitation-dependent property, the therapeutic outcome is unreliable when the treatment zone lacks cavitation nuclei. To overcome this intrinsic limitation, we introduced perfluorocarbon nanodroplets as extra cavitation nuclei into short-pulsed HIFU-mediated thermal ablation. Two types of nanodroplets were used with perfluorohexane (PFH) as the core material coated with bovine serum albumin (BSA) or an anionic fluorosurfactant (FS) to demonstrate the feasibility of this study. The thermal ablation process was recorded by high-speed photography. The inertial cavitation activity during the ablation was revealed by sonoluminescence (SL). The high-speed photography results show that the thermal ablation volume increased by ∼643% and 596% with BSA-PFH and FS-PFH, respectively, than the short-pulsed HIFU alone at an acoustic power of 19.5 W. Using nanodroplets, much larger ablation volumes were created even at a much lower acoustic power. Meanwhile, the treatment time for ablating a desired volume significantly reduced in the presence of nanodroplets. Moreover, by adjusting the treatment time, lesion migration towards the HIFU transducer could also be avoided. The SL results show that the thermal lesion shape was significantly dependent on the inertial cavitation in this short-pulsed HIFU-mediated thermal ablation. The inertial cavitation activity became more predictable by using nanodroplets. Therefore, the introduction of PFH nanodroplets as extra cavitation nuclei made the short-pulsed HIFU thermal ablation more efficient by increasing the ablation volume and speed, and more controllable by reducing the acoustic power and preventing lesion migration. Copyright © 2018. Published by Elsevier B.V.

Antitumor bystander effect induced by radiation-inducible target gene therapy combined with α particle irradiation

International Nuclear Information System (INIS)

Liu Hui; Jin Chufeng; Wu Yican; Ge Shenfang; Wu Lijun; FDS Team

2012-01-01

In this work, we investigated the bystander effect of the tumor and normal cells surrounding the target region caused by radiation-inducible target gene therapy combined with α-particle irradiation. The receptor tumor cell A549 and normal cell MRC-5 were co-cultured with the donor cells irradiated to 0.5 Gy or the non-irradiated donor cells, and their survival and apoptosis fractions were evaluated. The results showed that the combined treatment of Ad-ET and particle irradiation could induce synergistic antitumor effect on A549 tumor cell, and the survival fraction of receptor cells co-cultured with the irradiated cells decreased by 6%, compared with receptor cells co-cultured with non-irradiated cells, and the apoptosis fraction increased in the same circumstance, but no difference was observed with the normal cells. This study demonstrates that Ad-ET combined with α-particle irradiation can significantly cause the bystander effect on neighboring tumor cells by inhibiting cell growth and inducing apoptosis, without obvious toxicity to normal cells. This suggests that combining radiation-inducible TRAIL gene therapy and irradiation may improve tumor treatment efficacy by specifically targeting tumor cells and even involving the neighboring tumor cells. (authors)

Hypoxia-Inducible Regulation of a Prodrug-Activating Enzyme for Tumor-Specific Gene Therapy

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Toru Shibata

2002-01-01

Full Text Available Previous studies have suggested that tumor hypoxia could be exploited for cancer gene therapy. Using hypoxia-responsive elements derived from the human vascular endothelial growth factor gene, we have generated vectors expressing a bacterial nitroreductase. (20NTR gene that can activate the anticancer prodrug CB1954. Stable transfectants of human HT1080 tumor cells with hypoxia-inducible vectors were established with G418 selection. Hypoxic induction of NTR protein correlated with increased sensitivity to in vitro exposure of HT 1080 cells to the prodrug. Growth delay assays were performed with established tumor xenografts derived from the same cells to detect the in vivo efficacy of CB1954 conversion to its cytotoxic form. Significant antitumor effects were achieved with intraperitoneal injections of CB1954 both in tumors that express NTR constitutively or with a hypoxia-inducible promoter. In addition, respiration of 10% O2 increased tumor hypoxia in vivo and enhanced the antitumor effects. Taken together, these results demonstrate that hypoxia-inducible vectors may be useful for tumor-selective gene therapy, although the problem of delivery of the vector to the tumors, particularly to the hypoxic cells in the tumors, is not addressed by these studies.

Modelling of the acoustic field of a multi-element HIFU array scattered by human ribs

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Gélat, Pierre; ter Haar, Gail; Saffari, Nader

2011-09-01

The efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a range of different cancers, including those of the liver, prostate and breast, has been demonstrated. As a non-invasive focused therapy, HIFU offers considerable advantages over techniques such as chemotherapy and surgical resection in terms of reduced risk of harmful side effects. Despite this, there are a number of significant challenges which currently hinder its widespread clinical application. One of these challenges is the need to transmit sufficient energy through the rib cage to induce tissue necrosis in the required volume whilst minimizing the formation of side lobes. Multi-element random-phased arrays are currently showing great promise in overcoming the limitations of single-element transducers. Nevertheless, successful treatment of a patient with liver tumours requires a thorough understanding of the way in which the ultrasonic pressure field from a HIFU array is scattered by the rib cage. In order to address this, a boundary element approach based on a generalized minimal residual (GMRES) implementation of the Burton-Miller formulation was used in conjunction with phase conjugation techniques to focus the field of a 256-element random HIFU array behind human ribs at locations requiring intercostal and transcostal treatment. Simulations were carried out on a 3D mesh of quadratic pressure patches generated using CT scan anatomical data for adult ribs 9-12 on the right side. The methodology was validated on spherical and cylindrical scatterers. Field calculations were also carried out for idealized ribs, consisting of arrays of strip-like scatterers, demonstrating effects of splitting at the focus. This method has the advantage of fully accounting for the effect of scattering and diffraction in 3D under continuous wave excitation.

Modelling of the acoustic field of a multi-element HIFU array scattered by human ribs

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Gelat, Pierre [National Physical Laboratory, Hampton Road, Teddington TW11 0LW (United Kingdom); Ter Haar, Gail [Therapeutic Ultrasound Group, Physics Department, Institute of Cancer Research, Sutton SM2 5NG (United Kingdom); Saffari, Nader, E-mail: Pierre.Gelat@npl.co.uk [Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE (United Kingdom)

2011-09-07

The efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a range of different cancers, including those of the liver, prostate and breast, has been demonstrated. As a non-invasive focused therapy, HIFU offers considerable advantages over techniques such as chemotherapy and surgical resection in terms of reduced risk of harmful side effects. Despite this, there are a number of significant challenges which currently hinder its widespread clinical application. One of these challenges is the need to transmit sufficient energy through the rib cage to induce tissue necrosis in the required volume whilst minimizing the formation of side lobes. Multi-element random-phased arrays are currently showing great promise in overcoming the limitations of single-element transducers. Nevertheless, successful treatment of a patient with liver tumours requires a thorough understanding of the way in which the ultrasonic pressure field from a HIFU array is scattered by the rib cage. In order to address this, a boundary element approach based on a generalized minimal residual (GMRES) implementation of the Burton-Miller formulation was used in conjunction with phase conjugation techniques to focus the field of a 256-element random HIFU array behind human ribs at locations requiring intercostal and transcostal treatment. Simulations were carried out on a 3D mesh of quadratic pressure patches generated using CT scan anatomical data for adult ribs 9-12 on the right side. The methodology was validated on spherical and cylindrical scatterers. Field calculations were also carried out for idealized ribs, consisting of arrays of strip-like scatterers, demonstrating effects of splitting at the focus. This method has the advantage of fully accounting for the effect of scattering and diffraction in 3D under continuous wave excitation.

MR-guided HIFU treatment of symptomatic uterine fibroids using novel feedback-regulated volumetric ablation: effectiveness and clinical practice.

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Ruhnke, H; Eckey, T; Bohlmann, M K; Beldoch, M P; Neumann, A; Agic, A; Hägele, J; Diedrich, K; Barkhausen, J; Hunold, P

2013-09-01

To evaluate a novel feedback-regulated volumetric sonication method in MR-guided HIFU treatment of symptomatic uterine fibroids. 27 fibroids with an average volume of 124.9 ± 139.8 cc in 18 women with symptomatic uterine fibroids were ablated using the new HIFU system Sonalleve (1.5 T MR system Achieva, Philips). 21 myomas in 13 women were reevaluated 6 months later. Standard (treatment) cells (TC) and feedback-regulated (feedback) cells (FC) with a diameter of 4, 8, 12, and 16 mm were used and compared concerning sonication success, diameter of induced necrosis, and maximum achieved temperature. The non-perfused volume ratio (NPV related to myoma volume) was quantified. The fibroid volume was measured before, 1 month, and 6 months after therapy. Symptoms were quantified using a specific questionnaire (UFS-QoL). In total, 205 TC and 227 FC were applied. The NPV ratio was 23 ± 15 % (2 - 55). The TC were slightly smaller than intended (-3.9 ± 52 %; range, -100 - 81), while the FC were 20.1 ± 25.3 % bigger (p = 0.02). Feedback mechanism is less diversifying in diameter (p feedback cells leads to more contiguous necrosis in diameter and a less diversifying temperature. ▶ MR-guided HIFU ablation of symptomatic uterine fibroids is a valuable treatment option. ▶ By non-invasive HIFU fibroid volumes can be reduced and symptoms improved. ▶ The novel feedback-regulated treatment cells offer advantages over standard treatment cells. © Georg Thieme Verlag KG Stuttgart · New York.

Prediction of HIFU Propagation in a Dispersive Medium via Khokhlov–Zabolotskaya–Kuznetsov Model Combined with a Fractional Order Derivative

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Shilei Liu

2018-04-01

Full Text Available High intensity focused ultrasound (HIFU has been proven to be promising in non-invasive therapies, in which precise prediction of the focused ultrasound field is crucial for its accurate and safe application. Although the Khokhlov–Zabolotskaya–Kuznetsov (KZK equation has been widely used in the calculation of the nonlinear acoustic field of HIFU, some deviations still exist when it comes to dispersive medium. This problem also exists as an obstacle to the Westervelt model and the Spherical Beam Equation. Considering that the KZK equation is the most prevalent model in HIFU applications due to its accurate and simple simulation algorithms, there is an urgent need to improve its performance in dispersive medium. In this work, a modified KZK (mKZK equation derived from a fractional order derivative is proposed to calculate the nonlinear acoustic field in a dispersive medium. By correcting the power index in the attenuation term, this model is capable of providing improved prediction accuracy, especially in the axial position of the focal area. Simulation results using the obtained model were further compared with the experimental results from a gel phantom. Good agreements were found, indicating the applicability of the proposed model. The findings of this work will be helpful in making more accurate treatment plans for HIFU therapies, as well as facilitating the application of ultrasound in acoustic hyperthermia therapy.

Non-invasive estimation of temperature using diagnostic ultrasound during HIFU therapy

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Georg, O.; Wilkens, V.

2017-03-01

The use of HIFU for thermal ablation of human tissues requires safe real-time monitoring of the lesion formation during the treatment to avoid damage of the surrounding healthy tissues and to control temperature rise. Besides MR imaging, several methods have been proposed for temperature imaging using diagnostic ultrasound, and echoshift estimation (using speckle tracking) is the most promising and commonly used technique. It is based on the thermal dependence of the ultrasound echo that accounts for two different physical phenomena: local change in speed of sound and thermal expansion of the propagating medium due to changes in temperature. In our experiments we have used two separate transducers: HIFU exposure was performed using a 1.06 MHz single element focusing transducer of 64 mm aperture and 63.2 mm focal length; the ultrasound diagnostic probe of 11 MHz operated in B-mode for image guidance. The temperature measurements were performed in an agar-based tissue-mimicking phantom. To verify the obtained results, numerical modeling of the acoustic and temperature fields was carried out using KZK and Pennes Bioheat equations, as well as measurements with thermocouples were performed.

Mechanism of the protective effects of long chain n-alkyl glucopyranosides against ultrasound-induced cytolysis of HL-60 cells

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Cheng, Jason Y.; Riesz, Peter

2007-01-01

Recently it has been shown that long chain (C5 to C8) n-alkyl glucopyranosides completely inhibit ultrasound-induced cytolysis [1]. This protective effect has possible applications in HIFU (high intensity focused ultrasound) for tumor treatment, and in ultrasound assisted drug delivery and gene therapy. n-Alkyl glucopyranosides with hexyl (5mM), heptyl (3mM), octyl (2mM) n-alkyl chains protected 100% of HL-60 cells in-vitro from 1.057 MHz ultrasound induced cytolysis under a range of conditio...

PASSIVE CAVITATION DETECTION DURING PULSED HIFU EXPOSURES OF EX VIVO TISSUES AND IN VIVO MOUSE PANCREATIC TUMORS

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Li, Tong; Chen, Hong; Khokhlova, Tatiana; Wang, Yak-Nam; Kreider, Wayne; He, Xuemei; Hwang, Joo Ha

2014-01-01

Pulsed high-intensity focused ultrasound (pHIFU) has been demonstrated to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rarefactional focal pressures (1–12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms, pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KPC mice and closely recapitulate human disease in their morphology. The cavitation threshold, defined at 50 % cavitation probability, was found to vary broadly among the investigated tissues (within 2.5–10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but ex vivo it decreased rapidly and stopped over the first few pulses

Passive cavitation detection during pulsed HIFU exposures of ex vivo tissues and in vivo mouse pancreatic tumors.

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Li, Tong; Chen, Hong; Khokhlova, Tatiana; Wang, Yak-Nam; Kreider, Wayne; He, Xuemei; Hwang, Joo Ha

2014-07-01

Pulsed high-intensity focused ultrasound (pHIFU) has been shown to enhance vascular permeability, disrupt tumor barriers and enhance drug penetration into tumor tissue through acoustic cavitation. Monitoring of cavitation activity during pHIFU treatments and knowing the ultrasound pressure levels sufficient to reliably induce cavitation in a given tissue are therefore very important. Here, three metrics of cavitation activity induced by pHIFU and evaluated by confocal passive cavitation detection were introduced: cavitation probability, cavitation persistence and the level of the broadband acoustic emissions. These metrics were used to characterize cavitation activity in several ex vivo tissue types (bovine tongue and liver and porcine adipose tissue and kidney) and gel phantoms (polyacrylamide and agarose) at varying peak-rare factional focal pressures (1-12 MPa) during the following pHIFU protocol: frequency 1.1 MHz, pulse duration 1 ms and pulse repetition frequency 1 Hz. To evaluate the relevance of the measurements in ex vivo tissue, cavitation metrics were also investigated and compared in the ex vivo and in vivo murine pancreatic tumors that develop spontaneously in transgenic KrasLSL.G12 D/+; p53 R172 H/+; PdxCretg/+ (KPC) mice and closely re-capitulate human disease in their morphology. The cavitation threshold, defined at 50% cavitation probability, was found to vary broadly among the investigated tissues (within 2.5-10 MPa), depending mostly on the water-lipid ratio that characterizes the tissue composition. Cavitation persistence and the intensity of broadband emissions depended both on tissue structure and lipid concentration. Both the cavitation threshold and broadband noise emission level were similar between ex vivo and in vivo pancreatic tumor tissue. The largest difference between in vivo and ex vivo settings was found in the pattern of cavitation occurrence throughout pHIFU exposure: it was sporadic in vivo, but it decreased rapidly and stopped

Adjuvant hormone therapy in patients undergoing high-intensity focused ultrasound therapy for locally advanced prostate cancer

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A. I. Neimark

2014-01-01

Full Text Available Objective: to evaluate the efficiency and safety of using the luteinizing hormone releasing hormone leuprorelin with the Atrigel delivery system in doses of 7.5, 22.5, and 45 mg as an adjuvant regimen in high- and moderate-risk cancer patients who have received high-intensity focused ultrasound (HIFU therapy.Subjects and methods. Moderate- and high-risk locally advanced prostate cancer (PC patients treated with HIFU (n = 28 and HIFU in combination with hormone therapy during 6 months (n = 31 were examined.Results. The investigation has shown that leuprorelin acetate monotherapy used within 6 months after HIFU therapy can achieve the highest reduction in prostate-specific antigen levels and positively affect the symptoms of the disease. HIFU in combination with androgen deprivation substantially diminishes the clinical manifestations of the disease and improves quality of life in HIFU-treated patients with PC, by reducing the degree of infravesical obstruction (according to uroflowmetric findings and IPSS scores, and causes a decrease in prostate volume as compared to those who have undergone HIFU only. Treatment with leuprorelin having the Atrigel delivery system has demonstrated the low incidence of adverse reactions and good tolerability.

Tissue lesion created by HIFU in continuous scanning mode

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Fan, Tingbo; Liu, Zhenbo; Zhang, Dong

2012-09-01

The lesion formation was numerically and experimentally investigated by the continuous scanning mode. Simulations were presented based on the combination of Khokhlov-Zabolotskaya-Kuznetov (KZK) equation and bio-heat equation. Measurements were performed on porcine liver tissues using a 1.01 MHz single-element focused transducer at various acoustic powers, confirmed the predicted results. Controlling of the peak temperature and lesion by the scanning speed may be exploited for improvement of efficiency in HIFU therapy.

In vivo preclinical evaluation of the accuracy of toroidal-shaped HIFU treatments using a tumor-mimic model

International Nuclear Information System (INIS)

N'Djin, W A; Melodelima, D; Parmentier, H; Chapelon, J Y; Rivoire, M

2010-01-01

The pig is an ideal animal model for preclinical evaluation of HIFU treatments, especially in the liver. However, there is no liver tumor model available for pigs. In this work, we propose to study an in vivo tumor-mimic model as a tool for evaluating if a sonographycally guided HIFU treatment, delivered by a toroidal-shaped device dedicated for the treatment of liver metastases, is correctly located in the liver. One centimeter tumor-mimics were created in liver tissues. These tumor-mimics were detectable on ultrasound imaging and on gross pathology. Two studies were carried out. First, an in vivo study of tolerance at mid-term (30 days, 10 pigs) revealed that tumor-mimics are suitable for studying HIFU treatments at a preclinical stage, since local and biological tolerances were excellent. The dimensions of the tumor-mimics were reproducible (diameter at day 0: 9.7 ± 2.0 mm) and were the same as a function of time (p = 0.64). A second in vivo study was carried out in ten pigs. Tumor mimics were used as targets in liver tissues in order to determine if the HIFU treatment is correctly located in the liver. A procedure of extensive HIFU ablation using multiple HIFU lesions juxtaposed manually was then tested on eight tumor-mimics. In 88% of the cases (seven out of eight), tumor-mimics were treated with negative margins (≥1 mm) in all directions. On average, negative margins measured 10.0 ± 6.7 mm. These tumor-mimics constitute an excellent reference for studying in vivo the accuracy of HIFU therapy in the liver.

Effect of hydrodynamic cavitation in the tissue erosion by pulsed high-intensity focused ultrasound (pHIFU)

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Zhou, Yufeng; Gao, Xiaobin Wilson

2016-09-01

High-intensity focused ultrasound (HIFU) is emerging as an effective therapeutic modality in clinics. Besides the thermal ablation, tissue disintegration is also possible because of the interaction between the distorted HIFU bursts and either bubble cloud or boiling bubble. Hydrodynamic cavitation is another type of cavitation and has been employed widely in industry, but its role in mechanical erosion to tissue is not clearly known. In this study, the bubble dynamics immediately after the termination of HIFU exposure in the transparent gel phantom was captured by high-speed photography, from which the bubble displacement towards the transducer and the changes of bubble size was quantitatively determined. The characteristics of hydrodynamic cavitation due to the release of the acoustic radiation force and relaxation of compressed surrounding medium were found to associate with the number of pulses delivered and HIFU parameters (i.e. pulse duration and pulse repetition frequency). Because of the initial big bubble (~1 mm), large bubble expansion (up to 1.76 folds), and quick bubble motion (up to ~1 m s-1) hydrodynamic cavitation is significant after HIFU exposure and may lead to mechanical erosion. The shielding effect of residual tiny bubbles would reduce the acoustic energy delivered to the pre-existing bubble at the focus and, subsequently, the hydrodynamic cavitation effect. Tadpole shape of mechanical erosion in ex vivo porcine kidney samples was similar to the contour of bubble dynamics in the gel. Liquefied tissue was observed to emit towards the transducer through the punctured tissue after HIFU exposure in the sonography. In summary, the release of HIFU exposure-induced hydrodynamic cavitation produces significant bubble expansion and motion, which may be another important mechanism of tissue erosion. Understanding its mechanism and optimizing the outcome would broaden and enhance HIFU applications.

Effect of hydrodynamic cavitation in the tissue erosion by pulsed high-intensity focused ultrasound (pHIFU).

Science.gov (United States)

Zhou, Yufeng; Gao, Xiaobin Wilson

2016-09-21

High-intensity focused ultrasound (HIFU) is emerging as an effective therapeutic modality in clinics. Besides the thermal ablation, tissue disintegration is also possible because of the interaction between the distorted HIFU bursts and either bubble cloud or boiling bubble. Hydrodynamic cavitation is another type of cavitation and has been employed widely in industry, but its role in mechanical erosion to tissue is not clearly known. In this study, the bubble dynamics immediately after the termination of HIFU exposure in the transparent gel phantom was captured by high-speed photography, from which the bubble displacement towards the transducer and the changes of bubble size was quantitatively determined. The characteristics of hydrodynamic cavitation due to the release of the acoustic radiation force and relaxation of compressed surrounding medium were found to associate with the number of pulses delivered and HIFU parameters (i.e. pulse duration and pulse repetition frequency). Because of the initial big bubble (~1 mm), large bubble expansion (up to 1.76 folds), and quick bubble motion (up to ~1 m s -1 ) hydrodynamic cavitation is significant after HIFU exposure and may lead to mechanical erosion. The shielding effect of residual tiny bubbles would reduce the acoustic energy delivered to the pre-existing bubble at the focus and, subsequently, the hydrodynamic cavitation effect. Tadpole shape of mechanical erosion in ex vivo porcine kidney samples was similar to the contour of bubble dynamics in the gel. Liquefied tissue was observed to emit towards the transducer through the punctured tissue after HIFU exposure in the sonography. In summary, the release of HIFU exposure-induced hydrodynamic cavitation produces significant bubble expansion and motion, which may be another important mechanism of tissue erosion. Understanding its mechanism and optimizing the outcome would broaden and enhance HIFU applications.

Development of radiation-inducible promoters for use in nitric oxide synthase gene therapy of cancer

International Nuclear Information System (INIS)

Hirst, D.G.; Worthington, J.; Adams, C.; Robson, T.; Scott, S.D.

2003-01-01

Full text: The free radical nitric oxide (NO) at nM concentrations performs multiple signaling roles that are essential for survival. These processes are regulated via the enzymes nNOS and eNOS, but another isoform, inducible nitric oxide synthase (iNOS) is capable of generating much higher concentrations (mM) over longer periods, resulting in the generation of very toxic species such as peroxynitrite. At high concentrations NO has many of the characteristics of an ideal anticancer molecule: it is cytotoxic (pro-apoptotic via peroxynitrite), it is a potent chemical radiosensitizer, it is anti-angiogenic and anti-metastatic. Thus, we see iNOS gene therapy as a strategy for targeting the generation of high concentrations of NO to tumours for therapeutic benefit. iNOS gene therapy should be used in combination with radiotherapy; so it is logical that the use of a radiation-inducible promoter should be part of the targeting strategy. We have tested several candidate promoters in vitro and in vivo. The WAF1 promoter has many of the properties desirable for therapeutic use including: rapid 3-4 fold induction at X-ray doses of 2 and 4Gy and no significant leakiness. WAF1 also has the advantage of being inducible by hypoxia and by the final product, NO. We have also tested the synthetic CArG promoter and demonstrated that, in addition to a high level of radiation inducibility, it is also inducible by NO. We have also been able to demonstrate potent radiosensitization (SER 2.0-2.5) in tumour cells in vitro and in vivo using iNOS gene transfer with constitutive or radiation-inducible promoters. We have also tested the use of iNOS gene therapy in combination with cisplatin and shown significant enhancement

MR-Guided Pulsed High-Intensity Focused Ultrasound Enhancement of Gene Therapy Combined With Androgen Deprivation and Radiotherapy for Prostate Cancer Treatment

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2009-09-01

ultrasound . J. Acoust. Soc.Am. 72 1926-1932, (1982) (7) Neppiras E A. Acoustic cavitation . Physics reports 61(3): 159-251, (1980) (8) ter Haar G R, Daniels...Guided Pulsed High-Intensity Focused Ultrasound Enhancement of 5b. GRANT NUMBER W81XWH-08-1-0469 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT...failing to This work is aimed to study MR guided high intensity focused ultrasound (MRgHIFU) enhancement of gene therapy for Prostate Cancer. The

Prediction of HIFU Propagation in a Dispersive Medium via Khokhlov–Zabolotskaya–Kuznetsov Model Combined with a Fractional Order Derivative

OpenAIRE

Shilei Liu; Yanye Yang; Chenghai Li; Xiasheng Guo; Juan Tu; Dong Zhang

2018-01-01

High intensity focused ultrasound (HIFU) has been proven to be promising in non-invasive therapies, in which precise prediction of the focused ultrasound field is crucial for its accurate and safe application. Although the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation has been widely used in the calculation of the nonlinear acoustic field of HIFU, some deviations still exist when it comes to dispersive medium. This problem also exists as an obstacle to the Westervelt model and the Spherical ...

Significant skin burns may occur with the use of a water balloon in HIFU treatment

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Ritchie, Robert; Collin, Jamie; Wu, Feng; Coussios, Constantin; Leslie, Tom; Cranston, David

2012-10-01

HIFU is a minimally-invasive therapy suitable for treating selected intra-abdominal tumors. Treatment is safe although skin burns may occur due to pre-focal heating. HIFU treatment of a renal transplant tumor located in the left lower abdomen was undertaken in our centre. Treatment was performed prone, requiring displacement of the abdominal wall away from the treatment field using a water balloon, constructed of natural rubber latex and filled with degassed water. Intra-operatively, ultrasound imaging and physical examination of the skin directly over the focal region was normal. Immediately post-operative, a full-thickness skin burn was evident at the periphery of the balloon location, outside the expected HIFU path. Three possibilities may account for this complication. Firstly, the water balloon may have acted as a lens, focusing the HIFU to a neo-focus off axis. Secondly, air bubbles may have been entrapped between the balloon and the skin, causing heating at the interface. Finally, heating of the isolated water within the balloon may have been sufficient to cause burning. In this case, the placement of a water balloon caused a significant skin burn. Care should be taken in their use as burns, situated off axis, may occur even if the overlying skin appears normal.

From Genomics to Gene Therapy: Induced Pluripotent Stem Cells Meet Genome Editing.

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Hotta, Akitsu; Yamanaka, Shinya

2015-01-01

The advent of induced pluripotent stem (iPS) cells has opened up numerous avenues of opportunity for cell therapy, including the initiation in September 2014 of the first human clinical trial to treat dry age-related macular degeneration. In parallel, advances in genome-editing technologies by site-specific nucleases have dramatically improved our ability to edit endogenous genomic sequences at targeted sites of interest. In fact, clinical trials have already begun to implement this technology to control HIV infection. Genome editing in iPS cells is a powerful tool and enables researchers to investigate the intricacies of the human genome in a dish. In the near future, the groundwork laid by such an approach may expand the possibilities of gene therapy for treating congenital disorders. In this review, we summarize the exciting progress being made in the utilization of genomic editing technologies in pluripotent stem cells and discuss remaining challenges toward gene therapy applications.

[High-intensity focused ultrasound (HIFU) for tumor pain relief in inoperable pancreatic cancer : Evaluation with the pain sensation scale (SES)].

Science.gov (United States)

Marinova, M; Strunk, H M; Rauch, M; Henseler, J; Clarens, T; Brüx, L; Dolscheid-Pommerich, R; Conrad, R; Cuhls, H; Radbruch, L; Schild, H H; Mücke, M

2017-02-01

High-intensity focused ultrasound (HIFU) in combination with palliative standard therapy is an innovative and effective treatment option for pain reduction in patients with inoperable pancreatic cancer. Evaluation of the effects of additive ultrasound (US)-guided HIFU treatment in inoperable pancreatic cancer on the sensory and affective pain perception using validated questionnaries. In this study 20 patients with locally advanced inoperable pancreatic cancer and tumor-related pain were treated by US-guided HIFU (6 stage III, 12 stage IV according to UICC and 2 with local recurrence after surgery). Ablation was performed using the JC HIFU system (HAIFU, Chongqing, China) with an ultrasonic device for real-time imaging. Clinical assessment included evaluation of pain severity using validated questionnaires with particular attention to the pain sensation scale (SES) with its affective and sensory component and the numeric rating scale (NRS). The average pain reduction after HIFU was 2.87 points on the NRS scale and 57.3 % compared to the mean baseline score (n = 15, 75 %) in 19 of 20 treated patients. Four patients did not report pain relief, however, the previous opioid medication could be stopped (n = 2) or the analgesic dosage could be reduced (n = 2). No pain reduction was achieved in one patient. Furthermore, after HIFU emotional as well as sensory pain aspects were significantly reduced (before vs. 1 week after HIFU, p pain scales). US-guided HIFU can be used for effective and early pain relief and reduction of emotional and sensory pain sensation in patients with locally advanced pancreatic cancer.

Tissue Necrosis Monitoring for HIFU Ablation with T1 Contrast MRI Imaging

Science.gov (United States)

Hwang, San-Chao; Yao, Ching; Kuo, Ih-Yuan; Tsai, Wei-Cheng; Chang, Hsu

2011-09-01

In MR-guided HIFU ablation, MTC (Magnetization Transfer Contrast) or perfusion imaging is usually used after ablation to evaluate the ablated area based on the thermally induced necrosis contrast. In our MR-guided HIFU ablation study, a T1 contrast MRI scan sequence has been used to distinguish between necrotic and non-necrotic tissue. The ablation of porcine meat in-vitro and in-vivo pig leg muscle show that the necrotic area of T1 contrast MRI image coincides with the photographs of sliced specimen. The sequence is considerably easier to apply than MTC or perfusion imaging, while giving good necrosis contrast. In addition, no injection of contrast agent is needed, allowing multiple scans to be applied throughout the entire ablation procedure.

Gene Therapy

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Gene therapy Overview Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease. Genes contain your ... that don't work properly can cause disease. Gene therapy replaces a faulty gene or adds a new ...

The role of numerical simulation for the development of an advanced HIFU system

Science.gov (United States)

Okita, Kohei; Narumi, Ryuta; Azuma, Takashi; Takagi, Shu; Matumoto, Yoichiro

2014-10-01

High-intensity focused ultrasound (HIFU) has been used clinically and is under clinical trials to treat various diseases. An advanced HIFU system employs ultrasound techniques for guidance during HIFU treatment instead of magnetic resonance imaging in current HIFU systems. A HIFU beam imaging for monitoring the HIFU beam and a localized motion imaging for treatment validation of tissue are introduced briefly as the real-time ultrasound monitoring techniques. Numerical simulations have a great impact on the development of real-time ultrasound monitoring as well as the improvement of the safety and efficacy of treatment in advanced HIFU systems. A HIFU simulator was developed to reproduce ultrasound propagation through the body in consideration of the elasticity of tissue, and was validated by comparison with in vitro experiments in which the ultrasound emitted from the phased-array transducer propagates through the acrylic plate acting as a bone phantom. As the result, the defocus and distortion of the ultrasound propagating through the acrylic plate in the simulation quantitatively agree with that in the experimental results. Therefore, the HIFU simulator accurately reproduces the ultrasound propagation through the medium whose shape and physical properties are well known. In addition, it is experimentally confirmed that simulation-assisted focus control of the phased-array transducer enables efficient assignment of the focus to the target. Simulation-assisted focus control can contribute to design of transducers and treatment planning.

Adiponectin gene therapy ameliorates high-fat, high-sucrose diet-induced metabolic perturbations in mice.

Science.gov (United States)

Kandasamy, A D; Sung, M M; Boisvenue, J J; Barr, A J; Dyck, J R B

2012-09-10

Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity.

Preclinical and clinical experience in vascular gene therapy: advantages over conservative/standard therapy.

Science.gov (United States)

Nikol, S; Huehns, T Y

2001-04-01

No systemic pharmacological treatment has been shown to convincingly reduce the incidence of restenosis after angioplasty or increase the formation of collaterals in ischemic tissue in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates or in inducing angiogenesis post-angioplasty and following stent implantation has encouraged the development of new technological treatment approaches. Gene therapy is a novel strategy with the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation, and to induce growth of new vessels or remodeling of pre-existing vessel branches, which may help patients with critical ischemia. Gene therapy strategies have the advantage of minimizing systemic side effects and may have a long-term effect as the encoded protein is released. Most clinical trials investigating gene therapy for vascular disease have been uncontrolled phase I and IIa trials. Gene therapy into vessels with the genes for growth factors has been demonstrated to be feasible and efficient. Local drug delivery devices have been used in combination with gene therapy in several trials to maximize safety and efficiency. Data from experimental animal work indicates that gene therapy may modify intimal hyperplasia after arterial injury, but there are few clinical trials on restenosis in patients. Preliminary clinical results show only limited success in altering restenosis rates. In vitro and experimental in vivo investigations into gene therapy for angiogenesis demonstrate increased formation of collaterals and functional improvement of limb ischemia. There is some evidence of increased collateral formation and clinical improvement in patients with critical limb ischemia. Results of placebo-controlled and double-blind trials of gene therapy for vascular disease are awaited.

Evaluation of temperature rise in a tissue mimicking material during HIFU exposure

International Nuclear Information System (INIS)

Maruvada, S; Liu, Y; Herman, B A; Harris, G R

2011-01-01

In pre-clinical testing it is essential to characterize clinical high intensity focused ultrasound (HIFU) devices using tissue-mimicking materials (TMMs) with well known characteristics, including temperature rise and cavitation properties. The purpose of this study was to monitor cavitation behavior and correlate its effect with temperature rise in a HIFU TMM containing an embedded thermocouple. A 75-μm fine wire thermocouple was embedded in a hydrogel-based TMM previously developed for HIFU. HIFU at 1.1 and 3.3 MHz was focused at the thermocouple junction. Focal pressures from 1-11 MPa were applied and the temperature profiles were recorded. Three hydrophones were used to monitor cavitation activity during sonication. A hydrophone confocal with the HIFU transducer and a cylindrical hydrophone lateral to the HIFU beam were used as passive cavitation detectors for spectral analysis of signals, and a needle hydrophone placed beyond the HIFU focus was used to record changes in the pressure amplitude due to blockage by bubbles at or near the focus. B-mode imaging scans were employed to visualize bubble presence during sonication. In a separate measurement, schlieren imaging was used to monitor the change in field distribution behind the TMM. All hydrophone methods correlated well with cavitation in the TMM.

Evaluation of temperature rise in a tissue mimicking material during HIFU exposure

Energy Technology Data Exchange (ETDEWEB)

Maruvada, S; Liu, Y; Herman, B A; Harris, G R, E-mail: subha.maruvada@fda.hhs.gov [Food and Drug Administration, Center for Devices and Radiological Health, 10903 New Hampshire Ave., Bldg., Silver Spring, MD 20993 (United States)

2011-02-01

In pre-clinical testing it is essential to characterize clinical high intensity focused ultrasound (HIFU) devices using tissue-mimicking materials (TMMs) with well known characteristics, including temperature rise and cavitation properties. The purpose of this study was to monitor cavitation behavior and correlate its effect with temperature rise in a HIFU TMM containing an embedded thermocouple. A 75-{mu}m fine wire thermocouple was embedded in a hydrogel-based TMM previously developed for HIFU. HIFU at 1.1 and 3.3 MHz was focused at the thermocouple junction. Focal pressures from 1-11 MPa were applied and the temperature profiles were recorded. Three hydrophones were used to monitor cavitation activity during sonication. A hydrophone confocal with the HIFU transducer and a cylindrical hydrophone lateral to the HIFU beam were used as passive cavitation detectors for spectral analysis of signals, and a needle hydrophone placed beyond the HIFU focus was used to record changes in the pressure amplitude due to blockage by bubbles at or near the focus. B-mode imaging scans were employed to visualize bubble presence during sonication. In a separate measurement, schlieren imaging was used to monitor the change in field distribution behind the TMM. All hydrophone methods correlated well with cavitation in the TMM.

Whole Body Bone Scan Findings after High Intensity Focused Ultrasound (HIFU) Treatment

International Nuclear Information System (INIS)

Seo, Ye Young; O, Joo Hyun; Sohn, Hyung Sun; Choi, Eun Kyoung; Yoo, Ik Dong; Oh, Jin Kyoung; Han, Eun Ji; Jung, Seung Eun; Kim, Sung Hoon

2011-01-01

This study aims to examine the findings of 99mT c diphosphonate bone scans in cancer patients with a history of HIFU treatment. Bone scan images of patients with a history of HIFU treatment for primary of metastatic cancer from January 2006 to July 2010 were retrospectively reviewed. Cases of primary bone tumor or HIFU treatment reaching only the superficial soft tissue layer were excluded. Bone scan images of 62 patients (26 female, 36 male; mean age 57±9 years) were studied. HIFU treatment was performed in the liver (n=40), pancreas (n=40), pancreas (n=16), and breast (n=6). Mean interval time between HIFU treatment and bone scan was 106±105 days (range: 1-572 days). Of 62 scans, 43 showed diffusely decreased uptake of bone within the path of HIFU treatment: antero axillary and/or posterior arcs of right 5th to 11th ribs in 34 cases after treatment of hepatic lesions; anterior arcs of 2nd to 5th ribs in 5 cases after treatment for breast tumors; and posterior arcs of left 9th to 11th ribs or thoraco lumbar vertebrae in 4 cases after treatment for pancreas tumor. Of 20 patients who had bone scans more than twice, five showed recovered uptake of the radiotracer in the involved ribs in the follow up bone scan. Of 62 bone scans in patients with a history of HIFU treatment for primary of metastatic cancer, 69% presented diffusely decreased uptake in the bone in the path of HIFU treatment.

Genes and Gene Therapy

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... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

Naked gene therapy of hepatocyte growth factor for dextran sulfate sodium-induced colitis in mice

International Nuclear Information System (INIS)

Kanbe, Takamasa; Murai, Rie; Mukoyama, Tomoyuki; Murawaki, Yoshiyuki; Hashiguchi, Ko-ichi; Yoshida, Yoko; Tsuchiya, Hiroyuki; Kurimasa, Akihiro; Harada, Ken-ichi; Yashima, Kazuo; Nishimuki, Eiji; Shabana, Noriko; Kishimoto, Yukihiro; Kojyo, Haruhiko; Miura, Kunihiko; Murawaki, Yoshikazu; Kawasaki, Hironaka; Shiota, Goshi

2006-01-01

Ulcerative colitis (UC) is progressive and relapsing disease. To explore the therapeutic effects of naked gene therapy of hepatocyte growth factor (HGF) on UC, the SRα promoter driving HGF gene was intrarectally administered to the mice in which colitis was induced by dextran sulfate sodium (DSS). Expression of the transgene was seen in surface epithelium, lamina propria, and muscularis mucosae. The HGF-treated mice showed reduced colonic mucosal damage and increased body weights, compared with control mice (P < 0.01 and P < 0.05, respectively). The HGF-treated mice displayed increased number of PCNA-positive cells and decreased number of apoptotic cells than in control mice (P < 0.01, each). Phosphorylated AKT was dramatically increased after HGF gene administration, however, phosphorylated ERK1/2 was not altered. Microarray analysis revealed that HGF induced expression of proliferation- and apoptosis-associated genes. These data suggest that naked HGF gene delivery causes therapeutic effects through regulation of many downstream genes

A New Clinical HIFU System (Teleson II)

Science.gov (United States)

Ma, Yixin; Symonds-Tayler, Richard; Rivens, Ian H.; ter Haar, Gail R.

2007-05-01

Previous clinical trials with our first prototype HIFU system (Teleson I) for the treatment of liver tumors, demonstrated a major challenge to be treatment of those tumors located behind the ribs. We have designed a new multi-element transducer for rib sparing. Initial simulation and experimental results (using a single channel power amplifier) are very encouraging. A new clinical HIFU system which can drive the multi-element transducer and control each channel independently is being designed and constructed. This second version of a clinical prototype HIFU system consists of a 3D motorised gantry, a multi-channel signal generator, a multi-channel power amplifier, a user interface PC, an embedded controller and auxiliary circuits for real-time interleaving/synchronization control and a to-be-implemented safety monitoring and data logging unit. For multi-element transducers, each element can be individually switched on and off for rib sparing, and phase and amplitude modulated for potential phased array applications. The multi-channel power amplifier can be switched on/off very rapidly at required intervals to interleave with ultrasound B-Scan imaging for HIFU monitoring or radiation force elastography imaging via a dedicated interleaving/timing module. The gantry movement can also be synchronised with power amplifier on/off and phase/amplitude updating for lesion generation under a wide variety of conditions including single lesions, lesion arrays and lesions "tracks" created whilst translating the active transducer. Results from testing the system using excised tissue will be presented.

Model-based ultrasound temperature visualization during and following HIFU exposure.

Science.gov (United States)

Ye, Guoliang; Smith, Penny Probert; Noble, J Alison

2010-02-01

This paper describes the application of signal processing techniques to improve the robustness of ultrasound feedback for displaying changes in temperature distribution in treatment using high-intensity focused ultrasound (HIFU), especially at the low signal-to-noise ratios that might be expected in in vivo abdominal treatment. Temperature estimation is based on the local displacements in ultrasound images taken during HIFU treatment, and a method to improve robustness to outliers is introduced. The main contribution of the paper is in the application of a Kalman filter, a statistical signal processing technique, which uses a simple analytical temperature model of heat dispersion to improve the temperature estimation from the ultrasound measurements during and after HIFU exposure. To reduce the sensitivity of the method to previous assumptions on the material homogeneity and signal-to-noise ratio, an adaptive form is introduced. The method is illustrated using data from HIFU exposure of ex vivo bovine liver. A particular advantage of the stability it introduces is that the temperature can be visualized not only in the intervals between HIFU exposure but also, for some configurations, during the exposure itself. 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

A framework for the correction of slow physiological drifts during MR-guided HIFU therapies : Proof of concept

NARCIS (Netherlands)

Zachiu, Cornel; de Senneville, Baudouin Denis; Moonen, Chrit; Ries, Mario

Purpose: While respiratory motion compensation for magnetic resonance (MR)-guided high intensity focused ultrasound (HIFU) interventions has been extensively studied, the influence of slow physiological motion due to, for example, peristaltic activity, has so far been largely neglected. During

The bystander effect of cancer gene therapy

International Nuclear Information System (INIS)

Lumniczky, K.; Safrany, G.

2008-01-01

Cancer gene therapy is a new, promising therapeutic agent. In the clinic, it should be used in combination with existing modalities, such as tumour irradiation. First, we summarise the most important fields of cancer gene therapy: gene directed enzyme pro-drug therapy; the activation of an anti-tumour immune attack; restoration of the wild type p53 status; the application of new, replication competent and oncolytic viral vectors; tumour specific, as well as radiation- and hypoxia-induced gene expression. Special emphasizes are put on the combined effect of these modalities with local tumour irradiation. Using the available vector systems, only a small portion of the cancer cells will contain the therapeutic genes under therapeutic situations. Bystander cell killing might contribute to the success of various gene therapy protocols. We summarise the evidences that lethal bystander effects may occur during cancer gene therapy. Bystander effects are especially important in the gene directed enzyme pro-drug therapy. There, bystander cell killing might have different routes: cell communication through gap junction intercellular contacts; release of toxic metabolites into the neighbourhood or to larger distances; phagocytosis of apoptotic bodies; and the activation of the immune system. Bystander cell killing can be enhanced by the introduction of gap junction proteins into the cells, by further activating the immune system with immune-stimulatory molecules, or by introducing genes into the cells that help the transfer of cytotoxic genes and / or metabolites into the bystander cells. In conclusion, there should be additional improvements in cancer gene therapy for the more efficient clinical application. (orig.)

An analytical solution for improved HIFU SAR estimation

International Nuclear Information System (INIS)

Dillon, C R; Vyas, U; Christensen, D A; Roemer, R B; Payne, A

2012-01-01

Accurate determination of the specific absorption rates (SARs) present during high intensity focused ultrasound (HIFU) experiments and treatments provides a solid physical basis for scientific comparison of results among HIFU studies and is necessary to validate and improve SAR predictive software, which will improve patient treatment planning, control and evaluation. This study develops and tests an analytical solution that significantly improves the accuracy of SAR values obtained from HIFU temperature data. SAR estimates are obtained by fitting the analytical temperature solution for a one-dimensional radial Gaussian heating pattern to the temperature versus time data following a step in applied power and evaluating the initial slope of the analytical solution. The analytical method is evaluated in multiple parametric simulations for which it consistently (except at high perfusions) yields maximum errors of less than 10% at the center of the focal zone compared with errors up to 90% and 55% for the commonly used linear method and an exponential method, respectively. For high perfusion, an extension of the analytical method estimates SAR with less than 10% error. The analytical method is validated experimentally by showing that the temperature elevations predicted using the analytical method's SAR values determined for the entire 3D focal region agree well with the experimental temperature elevations in a HIFU-heated tissue-mimicking phantom. (paper)

A User-Friendly Software Package for HIFU Simulation

Science.gov (United States)

Soneson, Joshua E.

2009-04-01

A freely-distributed, MATLAB (The Mathworks, Inc., Natick, MA)-based software package for simulating axisymmetric high-intensity focused ultrasound (HIFU) beams and their heating effects is discussed. The package (HIFU_Simulator) consists of a propagation module which solves the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation and a heating module which solves Pennes' bioheat transfer (BHT) equation. The pressure, intensity, heating rate, temperature, and thermal dose fields are computed, plotted, the output is released to the MATLAB workspace for further user analysis or postprocessing.

Non-Thermal High-Intensity Focused Ultrasound for Breast Cancer Therapy

Science.gov (United States)

2013-07-01

Comet assay reveals DNA strand breaks induced by ultrasonic cavitation in vitro, Ultrasound in medicine & biology 1995; 21: 841-8. 3. Dalecki D...doxorubicin, focused ultrasound , HIFU, prostate cancer I. INTRODUCTION Pulsed high-intensity focused ultrasound (pFUS) is able to create acoustic cavitation ... ultrasound for breast cancer therapy PRINCIPAL INVESTIGATOR: Chang Ming (Charlie) Ma, Ph.D

Interference-free ultrasound imaging during HIFU therapy, using software tools

Science.gov (United States)

Vaezy, Shahram (Inventor); Held, Robert (Inventor); Sikdar, Siddhartha (Inventor); Managuli, Ravi (Inventor); Zderic, Vesna (Inventor)

2010-01-01

Disclosed herein is a method for obtaining a composite interference-free ultrasound image when non-imaging ultrasound waves would otherwise interfere with ultrasound imaging. A conventional ultrasound imaging system is used to collect frames of ultrasound image data in the presence of non-imaging ultrasound waves, such as high-intensity focused ultrasound (HIFU). The frames are directed to a processor that analyzes the frames to identify portions of the frame that are interference-free. Interference-free portions of a plurality of different ultrasound image frames are combined to generate a single composite interference-free ultrasound image that is displayed to a user. In this approach, a frequency of the non-imaging ultrasound waves is offset relative to a frequency of the ultrasound imaging waves, such that the interference introduced by the non-imaging ultrasound waves appears in a different portion of the frames.

Real-time temperature estimation and monitoring of HIFU ablation through a combined modeling and passive acoustic mapping approach

International Nuclear Information System (INIS)

Jensen, C R; Cleveland, R O; Coussios, C C

2013-01-01

Passive acoustic mapping (PAM) has been recently demonstrated as a method of monitoring focused ultrasound therapy by reconstructing the emissions created by inertially cavitating bubbles (Jensen et al 2012 Radiology 262 252–61). The published method sums energy emitted by cavitation from the focal region within the tissue and uses a threshold to determine when sufficient energy has been delivered for ablation. The present work builds on this approach to provide a high-intensity focused ultrasound (HIFU) treatment monitoring software that displays both real-time temperature maps and a prediction of the ablated tissue region. This is achieved by determining heat deposition from two sources: (i) acoustic absorption of the primary HIFU beam which is calculated via a nonlinear model, and (ii) absorption of energy from bubble acoustic emissions which is estimated from measurements. The two sources of heat are used as inputs to the bioheat equation that gives an estimate of the temperature of the tissue as well as estimates of tissue ablation. The method has been applied to ex vivo ox liver samples and the estimated temperature is compared to the measured temperature and shows good agreement, capturing the effect of cavitation-enhanced heating on temperature evolution. In conclusion, it is demonstrated that by using PAM and predictions of heating it is possible to produce an evolving estimate of cell death during exposure in order to guide treatment for monitoring ablative HIFU therapy. (paper)

The potential of high intensity focused ultrasound (HIFU) combine phase-sensitive optical coherence tomography (PhS-OCT) for diseases diagnosis, treatment and monitoring

Science.gov (United States)

Zhou, Kanheng; Wang, Yan; Feng, Kairui; Li, Chunhui; Huang, Zhihong

2018-02-01

HIFU is a truly noninvasive, acoustic therapeutic technique that utilizes high intensity acoustic field in the focus to kill the targeted tissue for disease treatment purpose. The mechanical properties of targeted tissue changes before and after treatment, and this change can be accurately detected by shear wave elastography. Hence, shear wave elastography is usually used for monitoring HIFU treatment asynchronously. To improve the low spatial resolution in ultrasound shear wave elastography, and to perform diseases diagnosis, treatment and monitoring in the same system, a new setup that combines HIFU and PhS-OCT system was proposed in this study. This proposed setup could do 1) HIFU treatment when the transducer works at high energy level, 2) ultrasound induced shear wave optical coherence elastography for HIFU treatment asynchronous monitoring when the transducer works at low energy level. Ex-vivo bovine liver tissue was treated at the same energy level for different time (0s, 1s, 5s, 9s) in this research. Elastography was performed on the lesion area of the sample after HIFU treatment, and the elastogram was reconstructed by the time of flight time method. The elastogram results clearly show the boundary of HIFU lesion area and surrounding normal tissue, even for 1s treatment time. And the average elasticity of the lesion grows linearly as the treatment time increases. Combined with OCT needle probe, the proposed method has a large potential not only to be used for superficial diseases treatment, but also to be used for high-precision-demanded diseases treatment, e.g. nervous disease treatment.

Induced pluripotency with endogenous and inducible genes

International Nuclear Information System (INIS)

Duinsbergen, Dirk; Eriksson, Malin; Hoen, Peter A.C. 't; Frisen, Jonas; Mikkers, Harald

2008-01-01

The recent discovery that two partly overlapping sets of four genes induce nuclear reprogramming of mouse and even human cells has opened up new possibilities for cell replacement therapies. Although the combination of genes that induce pluripotency differs to some extent, Oct4 and Sox2 appear to be a prerequisite. The introduction of four genes, several of which been linked with cancer, using retroviral approaches is however unlikely to be suitable for future clinical applications. Towards developing a safer reprogramming protocol, we investigated whether cell types that express one of the most critical reprogramming genes endogenously are predisposed to reprogramming. We show here that three of the original four pluripotency transcription factors (Oct4, Klf4 and c-Myc or MYCER TAM ) induced reprogramming of mouse neural stem (NS) cells exploiting endogenous SoxB1 protein levels in these cells. The reprogrammed neural stem cells differentiated into cells of each germ layer in vitro and in vivo, and contributed to mouse development in vivo. Thus a combinatorial approach taking advantage of endogenously expressed genes and inducible transgenes may contribute to the development of improved reprogramming protocols

The feasibility and safety of high-intensity focused ultrasound combined with low-dose external beam radiotherapy as supplemental therapy for advanced prostate cancer following hormonal therapy.

Science.gov (United States)

Wu, Rui-Yi; Wang, Guo-Min; Xu, Lei; Zhang, Bo-Heng; Xu, Ye-Qing; Zeng, Zhao-Chong; Chen, Bing

2011-05-01

The aim of this study was to investigate the feasibility and safety of high-intensity focused ultrasound (HIFU) combined with (+) low-dose external beam radiotherapy (LRT) as supplemental therapy for advanced prostate cancer (PCa) following hormonal therapy (HT). Our definition of HIFU+LRT refers to treating primary tumour lesions with HIFU in place of reduced field boost irradiation to the prostate, while retaining four-field box irradiation to the pelvis in conventional-dose external beam radiotherapy (CRT). We performed a prospective, controlled and non-randomized study on 120 patients with advanced PCa after HT who received HIFU, CRT, HIFU+LRT and HT alone, respectively. CT/MR imaging showed the primary tumours and pelvic lymph node metastases visibly shrank or even disappeared after HIFU+LRT treatment. There were significant differences among four groups with regard to overall survival (OS) and disease-specific survival (DSS) curves (P = 0.018 and 0.015). Further comparison between each pair of groups suggested that the long-term DSS of the HIFU+LRT group was higher than those of the other three groups, but there was no significant difference between the HIFU+LRT group and the CRT group. Multivariable Cox's proportional hazard model showed that both HIFU+LRT and CRT were independently associated with DSS (P = 0.001 and 0.035) and had protective effects with regard to the risk of death. Compared with CRT, HIFU+LRT significantly decreased incidences of radiation-related late gastrointestinal (GI) and genitourinary (GU) toxicity grade ≥ II. In conclusion, long-term survival of patients with advanced PCa benefited from strengthening local control of primary tumour and regional lymph node metastases after HT. As an alternative to CRT, HIFU+LRT showed good efficacy and better safety.

Imaging gene expression in gene therapy

International Nuclear Information System (INIS)

Wiebe, Leonard I.

1997-01-01

Full text. Gene therapy can be used to introduce new genes, or to supplement the function of indigenous genes. At the present time, however, there is non-invasive test to demonstrate efficacy of the gene transfer and expression processes. It has been postulated that scintigraphic imaging can offer unique information on both the site at which the transferred gene is expressed, and the degree of expression, both of which are critical issue for safety and clinical efficacy. Many current studies are based on 'suicide gene therapy' of cancer. Cells modified to express these genes commit metabolic suicide in the presence of an enzyme encoded by the transferred gene and a specifically-convertible pro drug. Pro drug metabolism can lead to selective metabolic trapping, required for scintigraphy. Herpes simplex virus type-1 thymidine kinase (H S V-1 t k + ) has been use for 'suicide' in vivo tumor gene therapy. It has been proposed that radiolabelled nucleosides can be used as radiopharmaceuticals to detect H S V-1 t k + gene expression where the H S V-1 t k + gene serves a reporter or therapeutic function. Animal gene therapy models have been studied using purine-([ 18 F]F H P G; [ 18 F]-A C V), and pyrimidine- ([ 123 / 131 I]I V R F U; [ 124 / 131I ]) antiviral nucleosides. Principles of gene therapy and gene therapy imaging will be reviewed and experimental data for [ 123 / 131I ]I V R F U imaging with the H S V-1 t k + reporter gene will be presented

Magnetic Resonance-Guided High-Intensity Focused Ultrasound (MRgHIFU) for Treatment of Symptomatic Uterine Fibroids: An Economic Analysis

Science.gov (United States)

Babashov, V; Palimaka, S; Blackhouse, G; O'Reilly, D

2015-01-01

Background Uterine fibroids, or leiomyomas, are the most common benign tumours in women of childbearing age. Some women experience symptoms (e.g., heavy bleeding) that require aggressive forms of treatment such as uterine artery embolization (UAE), myomectomy, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), and even hysterectomy. It is important to note that hysterectomy is not appropriate for women who desire future childbearing. Objectives The objective of this analysis was to evaluate the cost-effectiveness and budgetary impact of implementing MRgHIFU as a treatment option for symptomatic uterine fibroids in premenopausal women for whom drugs have been ineffective. Review Methods We performed an original cost-effectiveness analysis to assess the long-term costs and effects of MRgHIFU compared with hysterectomy, myomectomy, and UAE as a strategy for treating symptomatic uterine fibroids in premenopausal women aged 40 to 51 years. We explored a number of scenarios, e.g., comparing MRgHIFU with uterine-preserving procedures only, considering MRgHIFU-eligible patients only, and eliminating UAE as a treatment option. In addition, we performed a one-year budget impact analysis, using data from Ontario administrative sources. Four scenarios were explored in the budgetary impact analysis: MRgHIFU funded at 2 centres MRgHIFU funded at 2 centres and replacing only uterine-preserving procedures MRgHIFU funded at 6 centres MRgHIFU funded at 6 centres and replacing only uterine-preserving procedures Analyses were conducted from the Ontario public payer perspective. Results The base case determined that the uterine artery embolization (UAE) treatment strategy was the cost-effective option at commonly accepted willingness-to-pay values. Compared with hysterectomy, UAE was calculated as having an incremental cost-effectiveness ratio (ICER) of $46,480 per quality-adjusted life-year (QALY) gained. The MRgHIFU strategy was extendedly dominated by a

Imaging gene expression in gene therapy

Energy Technology Data Exchange (ETDEWEB)

Wiebe, Leonard I. [Alberta Univ., Edmonton (Canada). Noujaim Institute for Pharmaceutical Oncology Research

1997-12-31

Full text. Gene therapy can be used to introduce new genes, or to supplement the function of indigenous genes. At the present time, however, there is non-invasive test to demonstrate efficacy of the gene transfer and expression processes. It has been postulated that scintigraphic imaging can offer unique information on both the site at which the transferred gene is expressed, and the degree of expression, both of which are critical issue for safety and clinical efficacy. Many current studies are based on `suicide gene therapy` of cancer. Cells modified to express these genes commit metabolic suicide in the presence of an enzyme encoded by the transferred gene and a specifically-convertible pro drug. Pro drug metabolism can lead to selective metabolic trapping, required for scintigraphy. Herpes simplex virus type-1 thymidine kinase (H S V-1 t k{sup +}) has been use for `suicide` in vivo tumor gene therapy. It has been proposed that radiolabelled nucleosides can be used as radiopharmaceuticals to detect H S V-1 t k{sup +} gene expression where the H S V-1 t k{sup +} gene serves a reporter or therapeutic function. Animal gene therapy models have been studied using purine-([{sup 18} F]F H P G; [{sup 18} F]-A C V), and pyrimidine- ([{sup 123}/{sup 131} I]I V R F U; [{sup 124}/{sup 131I}]) antiviral nucleosides. Principles of gene therapy and gene therapy imaging will be reviewed and experimental data for [{sup 123}/{sup 131I}]I V R F U imaging with the H S V-1 t k{sup +} reporter gene will be presented

Gene therapy and radionuclides targeting therapy in mammary carcinoma

International Nuclear Information System (INIS)

Song Jinhua

2003-01-01

Breast carcinoma's gene therapy is a hotspot in study of the tumor's therapy in the recent years. Currently the major therapy methods that in the experimentative and primary clinical application phases include immunological gene therapy, multidrug resistance gene therapy, antisense oligonucleotide therapy and suicide gene therapy. The gene targeting brachytherapy, which is combined with gene therapy and radiotherapy has enhanced the killer effects of the suicide gene and nuclide in tumor cells. That has break a new path in tumor's gene therapy. The further study in this field will step up it's space to the clinical application

Reporter gene imaging: potential impact on therapy

International Nuclear Information System (INIS)

Serganova, Inna; Blasberg, Ronald

2005-01-01

Positron emission tomography (PET)-based molecular-genetic imaging in living organisms has enjoyed exceptional growth over the past 5 years; this is particularly striking since it has been identified as a new discipline only within the past decade. Positron emission tomography is one of three imaging technologies (nuclear, magnetic resonance and optical) that has begun to incorporate methods that are established in molecular and cell biology research. The convergence of these disciplines and the wider application of multi-modality imaging are at the heart of this success story. Most current molecular-genetic imaging strategies are 'indirect,' coupling a 'reporter gene' with a complimentary 'reporter probe.' Reporter gene constructs can be driven by constitutive promoter elements and used to monitor gene therapy vectors and the efficacy of trans gene targeting and transduction, as well as to monitor adoptive cell-based therapies. Inducible promoters can be used as 'sensors' to regulate the magnitude of reporter gene expression and can be used to provide information about endogenous cell processes. Reporter systems can also be constructed to monitor mRNA stabilization and specific protein-protein interactions. Promoters can be cell specific and restrict transgene expression to certain tissue and organs. The translation of reporter gene imaging to specific clinical applications is discussed. Several examples that have potential for patient imaging studies in the near future include monitoring adenoviral-based gene therapy, oncolytic herpes virus therapy, adoptive cell-based therapies and Salmonella-based tumor-targeted cancer therapy and imaging. The primary translational applications of noninvasive in vivo reporter gene imaging are likely to be (a) quantitative monitoring of the gene therapy vector and the efficacy of transduction in clinical protocols, by imaging the location, extent and duration of transgene expression; (b) monitoring cell trafficking, targeting

Radionuclide reporter gene imaging for cardiac gene therapy

International Nuclear Information System (INIS)

Inubushi, Masayuki; Tamaki, Nagara

2007-01-01

In the field of cardiac gene therapy, angiogenic gene therapy has been most extensively investigated. The first clinical trial of cardiac angiogenic gene therapy was reported in 1998, and at the peak, more than 20 clinical trial protocols were under evaluation. However, most trials have ceased owing to the lack of decisive proof of therapeutic effects and the potential risks of viral vectors. In order to further advance cardiac angiogenic gene therapy, remaining open issues need to be resolved: there needs to be improvement of gene transfer methods, regulation of gene expression, development of much safer vectors and optimisation of therapeutic genes. For these purposes, imaging of gene expression in living organisms is of great importance. In radionuclide reporter gene imaging, ''reporter genes'' transferred into cell nuclei encode for a protein that retains a complementary ''reporter probe'' of a positron or single-photon emitter; thus expression of the reporter genes can be imaged with positron emission tomography or single-photon emission computed tomography. Accordingly, in the setting of gene therapy, the location, magnitude and duration of the therapeutic gene co-expression with the reporter genes can be monitored non-invasively. In the near future, gene therapy may evolve into combination therapy with stem/progenitor cell transplantation, so-called cell-based gene therapy or gene-modified cell therapy. Radionuclide reporter gene imaging is now expected to contribute in providing evidence on the usefulness of this novel therapeutic approach, as well as in investigating the molecular mechanisms underlying neovascularisation and safety issues relevant to further progress in conventional gene therapy. (orig.)

Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

Directory of Open Access Journals (Sweden)

Mavroudi M

2014-01-01

Full Text Available Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The grim statistics speak for themselves with reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem guided gene therapy. Stem cells have the unique potential for self-renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we

New tools in regenerative medicine: gene therapy.

Science.gov (United States)

Muñoz Ruiz, Miguel; Regueiro, José R

2012-01-01

Gene therapy aims to transfer genetic material into cells to provide them with new functions. A gene transfer agent has to be safe, capable of expressing the desired gene for a sustained period of time in a sufficiently large population of cells to produce a biological effect. Identifying a gene transfer tool that meets all of these criteria has proven to be a difficult objective. Viral and nonviral vectors, in vivo, ex vivo and in situ strategies co-exist at present, although ex vivo lenti-or retroviral vectors are presently the most popular.Natural stem cells (from embryonic, hematopoietic, mesenchymal, or adult tissues) or induced progenitor stem (iPS) cells can be modified by gene therapy for use in regenerative medicine. Among them, hematopoietic stem cells have shown clear clinical benefit, but iPS cells hold humongous potential with no ethical concerns.

Measurement of feline cytokines interleukin-12 and interferon- g produced by heat inducible gene therapy adenoviral vector using real time PCR

International Nuclear Information System (INIS)

Siddiqui, F.; Avery, P.R.; Ullrich, R.L.; LaRue, S.M.; Dewhirst, M.W.; Li, C.-Y.

2003-01-01

Biologic tumor therapy using Interleukin-12 (IL-12) has shown promise as an adjuvant to radiation therapy. The goals for cancer gene immunotherapy include effective eradication of established tumors and generation of a lasting systemic immune response. Among the cytokines, IL-12 has been found to be most effective gene in eradicating experimental tumors, preventing the development of metastases, and eliciting long-term antitumor immunity. Depending on the tumor model, IL-12 can exert antitumor activities via T cells, NK cells or NKT cells. It induces the production of IFN-g and IFN-inducible protein-10. It is also postulated to have antiangiogenic effects, thus inhibiting tumor formation and metastases. However, its use in clinical trials has been restricted largely owing to its systemic hematologic and hepatotoxicity. We tested the efficacy of adenovirus mediated expression of feline IL-12 gene placed under the control of an inducible promoter, the heat shock proteins (hsp70B). This places gene expression under the control of an external physical agent (hyperthermia), thus offering an 'on-off' switch and potentially reducing systemic toxicity by restricting its expression locally to the tumor. Crandell Feline Kidney (CrFK) cells were infected using the construct and the supernatant was then used to stimulate production of interferon g (IFN-g) in feline peripheral blood mononuclear cells (PBMC). As there is no commercially available ELISA kit currently available to detect or measure feline cytokines, we used real time-PCR to measure cytokine mRNA. These results will be used to initiate a clinical trial in cats with soft tissue sarcomas examining hyperthermia Induced gene therapy in conjunction with radiation therapy. The real time- PCR techniques developed here will be used to quantitatively measure cytokine mRNA levels in the punch biopsy samples obtained from the cats during the clinical trial. Support for this study was in part by NCI grant CA72745

Terapia gênica Gene therapy

Directory of Open Access Journals (Sweden)

Nance Beyer Nardi

2002-01-01

Full Text Available Terapia gênica é um procedimento médico que envolve a modificação genética de células como forma de tratar doenças. Os genes influenciam praticamente todas as doenças humanas, seja pela codificação de proteínas anormais diretamente responsáveis pela doença, seja por determinar suscetibilidade a agentes ambientais que a induzem. A terapia gênica é ainda experimental, e está sendo estudada em protocolos clínicos para diferentes tipos de doenças. O desenvolvimento de métodos seguros e eficientes de transferência gênica para células humanas é um dos pontos mais importantes na terapia gênica. Apesar do grande esforço dirigido na última década para o aperfeiçoamento dos protocolos de terapia gênica humana, e dos avanços importantes na pesquisa básica, as aplicações terapêuticas da tecnologia de transferência gênica continuam ainda em grande parte teóricas. O potencial da terapia gênica é muito grande, devendo ainda causar grande impacto em todos os aspectos da medicina.Gene therapy is a medical intervention that involves modifying the genetic material of living cells to fight disease. Genes influence virtually every human disease, either by encoding for abnormal proteins, which are directly responsible for the disease, or by causing a susceptibility to environmental agents which induce it. Gene therapy is still experimental, and is being studied in clinical trials for many different types of diseases. The development of safe and effective methods of implanting normal genes into the human cell is one of the most important technical issues in gene therapy. Although much effort has been directed in the last decade toward improvement of protocols in human gene therapy, and in spite of many considerable achievements in basic research, the therapeutic applications of gene transfer technology still remain mostly theoretical. The potential for gene therapy is huge and likely to impact on all aspects of medicine.

History of gene therapy.

Science.gov (United States)

Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

2013-08-10

Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality. Copyright © 2013 Elsevier B.V. All rights reserved.

Gene expression and gene therapy imaging

International Nuclear Information System (INIS)

Rome, Claire; Couillaud, Franck; Moonen, Chrit T.W.

2007-01-01

The fast growing field of molecular imaging has achieved major advances in imaging gene expression, an important element of gene therapy. Gene expression imaging is based on specific probes or contrast agents that allow either direct or indirect spatio-temporal evaluation of gene expression. Direct evaluation is possible with, for example, contrast agents that bind directly to a specific target (e.g., receptor). Indirect evaluation may be achieved by using specific substrate probes for a target enzyme. The use of marker genes, also called reporter genes, is an essential element of MI approaches for gene expression in gene therapy. The marker gene may not have a therapeutic role itself, but by coupling the marker gene to a therapeutic gene, expression of the marker gene reports on the expression of the therapeutic gene. Nuclear medicine and optical approaches are highly sensitive (detection of probes in the picomolar range), whereas MRI and ultrasound imaging are less sensitive and require amplification techniques and/or accumulation of contrast agents in enlarged contrast particles. Recently developed MI techniques are particularly relevant for gene therapy. Amongst these are the possibility to track gene therapy vectors such as stem cells, and the techniques that allow spatiotemporal control of gene expression by non-invasive heating (with MRI guided focused ultrasound) and the use of temperature sensitive promoters. (orig.)

Radiotechnologies and gene therapy

International Nuclear Information System (INIS)

Xia Jinsong

2001-01-01

Gene therapy is an exciting frontier in medicine today. Radiologist will make an uniquely contribution to these exciting new technologies at every level by choosing sites for targeting therapy, perfecting and establishing routes of delivery, developing imaging strategies to monitor therapy and assess gene expression, developing radiotherapeutic used of gene therapy

Advances in Viral Vector-Based TRAIL Gene Therapy for Cancer

International Nuclear Information System (INIS)

Norian, Lyse A.; James, Britnie R.; Griffith, Thomas S.

2011-01-01

Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic

TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

Energy Technology Data Exchange (ETDEWEB)

Ferrara, K. [University of California - Davis (United States)

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imaging Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.

TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

International Nuclear Information System (INIS)

Ferrara, K.

2015-01-01

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imaging Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare

Tumor targeted gene therapy

International Nuclear Information System (INIS)

Kang, Joo Hyun

2006-01-01

Knowledge of molecular mechanisms governing malignant transformation brings new opportunities for therapeutic intervention against cancer using novel approaches. One of them is gene therapy based on the transfer of genetic material to an organism with the aim of correcting a disease. The application of gene therapy to the cancer treatment had led to the development of new experimental approaches such as suicidal gene therapy, inhibition of oncogenes and restoration of tumor-suppressor genes. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a prodrug into a toxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and cytosine deaminase (CD). Especially, physicians and scientists of nuclear medicine field take an interest in suicidal gene therapy because they can monitor the location and magnitude, and duration of expression of HSV1-tk and CD by PET scanner

Understanding and Prevention of “Therapy-” Induced Dyskinesias

Directory of Open Access Journals (Sweden)

Iciar Aviles-Olmos

2012-01-01

Full Text Available L-dopa is the most effective, currently available treatment for Parkinson’s disease (PD, but it leads to the development of involuntary movements known as L-dopa-induced dyskinesia (LID in the majority of patients after long-term use. Both gene and cell therapy approaches are the subject of multiple ongoing studies as potential ways of relieving symptoms of PD without the complication of dyskinesia. However, the spectre of dyskinesia in the absence of L-dopa, the so-called “off-phase” or graft-induced dyskinesia (GID, remains a major obstacle particularly in the further development of cell therapy in PD, but it is also a concern for proponents of gene therapy approaches. LID results from nonphysiological dopamine release, supersensitivity of dopamine receptors, and consequent abnormal signalling through mechanisms of synaptic plasticity. Restoration of physiological circuitry within the basal ganglia loops is ultimately the aim of all cell and gene therapy approaches but each using distinctive strategies and accompanied by risks of exacerbation of LID or development of “off-phase”/GID. In this paper we discuss the details of what is understood regarding the development of dyskinesias with relevance to cell and gene therapy and potential strategies to minimize their occurrence.

Influence of cavitation bubble growth by rectified diffusion on cavitation-enhanced HIFU

Science.gov (United States)

Okita, Kohei; Sugiyama, Kazuyasu; Takagi, Shu; Matsumoto, Yoichiro

2017-11-01

Cavitation is becoming increasingly important in therapeutic ultrasound applications such as diagnostic, tumor ablation and lithotripsy. Mass transfer through gas-liquid interface due to rectified diffusion is important role in an initial stage of cavitation bubble growth. In the present study, influences of the rectified diffusion on cavitation-enhanced high-intensity focused ultrasound (HIFU) was investigated numerically. Firstly, the mass transfer rate of gas from the surrounding medium to the bubble was examined as function of the initial bubble radius and the driving pressure amplitude. As the result, the pressure required to bubble growth was decreases with increasing the initial bubble radius. Next, the cavitation-enhanced HIFU, which generates cavitation bubbles by high-intensity burst and induces the localized heating owing to cavitation bubble oscillation by low-intensity continuous waves, was reproduced by the present simulation. The heating region obtained by the simulation is agree to the treatment region of an in vitro experiment. Additionally, the simulation result shows that the localized heating is enhanced by the increase of the equilibrium bubble size due to the rectified diffusion. This work was supported by JSPS KAKENHI Grant Numbers JP26420125,JP17K06170.

Stem cell and gene therapies for diabetes mellitus.

Science.gov (United States)

Calne, Roy Y; Gan, Shu Uin; Lee, Kok Onn

2010-03-01

In this Perspectives article, we comment on the progress in experimental stem cell and gene therapies that might one day become a clinical reality for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Finally, gene therapy shows some promise for the generation of insulin-producing cells. Here, we discuss two of the most frequently used approaches: in vitro gene delivery into cells which are then transplanted into the recipient and direct delivery of genes in vivo.

Bifidobacterial recombinant thymidine kinase-ganciclovir gene therapy system induces FasL and TNFR2 mediated antitumor apoptosis in solid tumors

International Nuclear Information System (INIS)

Wang, Changdong; Ma, Yongping; Hu, Qiongwen; Xie, Tingting; Wu, Jiayan; Zeng, Fan; Song, Fangzhou

2016-01-01

Directly targeting therapeutic suicide gene to a solid tumor is a hopeful approach for cancer gene therapy. Treatment of a solid tumor by an effective vector for a suicide gene remains a challenge. Given the lack of effective treatments, we constructed a bifidobacterial recombinant thymidine kinase (BF-rTK) -ganciclovir (GCV) targeting system (BKV) to meet this requirement and to explore antitumor mechanisms. Bifidobacterium (BF) or BF-rTK was injected intratumorally with or without ganciclovir in a human colo320 intestinal xenograft tumor model. The tumor tissues were analyzed using apoptosis antibody arrays, real time PCR and western blot. The colo320 cell was analyzed by the gene silencing method. Autophagy and necroptosis were also detected in colo320 cell. Meanwhile, three human digestive system xenograft tumor models (colorectal cancer colo320, gastric cancer MKN-45 and liver cancer SSMC-7721) and a breast cancer (MDA-MB-231) model were employed to validate the universality of BF-rTK + GCV in solid tumor gene therapy. The survival rate was evaluated in three human cancer models after the BF-rTK + GCV intratumor treatment. The analysis of inflammatory markers (TNF-α) in tumor indicated that BF-rTK + GCV significantly inhibited TNF-α expression. The results suggested that BF-rTK + GCV induced tumor apoptosis without autophagy and necroptosis occurrence. The apoptosis was transduced by multiple signaling pathways mediated by FasL and TNFR2 and mainly activated the mitochondrial control of apoptosis via Bid and Bim, which was rescued by silencing Bid or/and Bim. However, BF + GCV only induced apoptosis via Fas/FasL signal pathway accompanied with increased P53 expression. We further found that BF-rTK + GCV inhibited the expression of the inflammatory maker of TNF-α. However, BF-rTK + GCV did not result in necroptosis and autophagy. BF-rTK + GCV induced tumor apoptosis mediated by FasL and TNFR2 through the mitochondrial control of apoptosis via Bid and Bim

Translational approach for gene therapy in epilepsy

DEFF Research Database (Denmark)

Ledri, Litsa Nikitidou; Melin, Esbjörn; Christiansen, Søren H.

2016-01-01

clinical trial for gene therapy of temporal lobe epilepsy was explored: We investigated (i) whether the post intrahippocampal kainate-induced status epilepticus (SE) model of chronic epilepsy in rats could be clinically relevant; and (ii) whether a translationally designed neuropeptide Y (NPY)/Y2 receptor...

Why commercialization of gene therapy stalled; examining the life cycles of gene therapy technologies.

Science.gov (United States)

Ledley, F D; McNamee, L M; Uzdil, V; Morgan, I W

2014-02-01

This report examines the commercialization of gene therapy in the context of innovation theories that posit a relationship between the maturation of a technology through its life cycle and prospects for successful product development. We show that the field of gene therapy has matured steadily since the 1980s, with the congruent accumulation of >35 000 papers, >16 000 US patents, >1800 clinical trials and >$4.3 billion in capital investment in gene therapy companies. Gene therapy technologies comprise a series of dissimilar approaches for gene delivery, each of which has introduced a distinct product architecture. Using bibliometric methods, we quantify the maturation of each technology through a characteristic life cycle S-curve, from a Nascent stage, through a Growing stage of exponential advance, toward an Established stage and projected limit. Capital investment in gene therapy is shown to have occurred predominantly in Nascent stage technologies and to be negatively correlated with maturity. Gene therapy technologies are now achieving the level of maturity that innovation research and biotechnology experience suggest may be requisite for efficient product development. Asynchrony between the maturation of gene therapy technologies and capital investment in development-focused business models may have stalled the commercialization of gene therapy.

Health-related quality of life after salvage high-intensity focused ultrasound (HIFU) treatment for locally radiorecurrent prostate cancer

International Nuclear Information System (INIS)

Berge, V.; Baco, E.; Dahl, A.A.; Karlsen, S.J.

2011-01-01

The objective of this study was to evaluate health-related quality of life (HRQOL) after salvage high-intensity focused ultrasound (HIFU) for locally radiorecurrent prostate cancer (PCa). Since June 2006 we have treated 61 patients consecutively by salvage HIFU. All patients were offered the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) questionnaire at baseline and at follow-up. Scores ranged from 0 (worst) to 100 (best). Clinically significant changes were defined as a minimum difference of 10 points between the baseline score and the score at follow-up. Fifty-seven patients (93%) had evaluable data at baseline, compared with 46 (75%) after treatment. The mean time lapse between HIFU treatment and questionnaire response was 17.5 months (range 6-29 months). The mean score for urinary function decreased from 79.7±12.1 prior to HIFU to 67.4±17.8 after HIFU (P<0.001). The mean score for sexual function decreased from 32.1±24.1 prior to HIFU to 17.2±17.0 after HIFU (P<0.001). There were no significant effects on bowel function. There was a significant reduction in the mean score for Physical HRQOL, but the mean score for Mental HRQOL was did not change significantly. Treatment of localized radiorecurrent PCa by salvage HIFU is associated with clinically significant reductions in urinary and sexual function domains after a mean follow-up of 17.5 months. (author)

Current Experimental Studies of Gene Therapy in Parkinson's Disease

Directory of Open Access Journals (Sweden)

Jing-ya Lin

2017-05-01

Full Text Available Parkinson's disease (PD was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration, the synthesis of neurotransmitter (for prolong the duration of L-dopa, and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD.

Gene therapy: An overview

Directory of Open Access Journals (Sweden)

Sudip Indu

2013-01-01

Full Text Available Gene therapy "the use of genes as medicine" involves the transfer of a therapeutic or working copy of a gene into specific cells of an individual in order to repair a faulty gene copy. The technique may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. The objective of gene therapy is to introduce new genetic material into target cells while causing no damage to the surrounding healthy cells and tissues, hence the treatment related morbidity is decreased. The delivery system includes a vector that delivers a therapeutic gene into the patient′s target cell. Functional proteins are created from the therapeutic gene causing the cell to return to a normal stage. The vectors used in gene therapy can be viral and non-viral. Gene therapy, an emerging field of biomedicine, is still at infancy and much research remains to be done before this approach to the treatment of condition will realize its full potential.

TU-B-210-00: MR-Guided Focused Ultrasound Therapy in Oncology

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-06-15

MR guided focused ultrasound (MRgFUS), or alternatively high-intensity focused ultrasound (MRgHIFU), is approved for thermal ablative treatment of uterine fibroids and pain palliation in bone metastases. Ablation of malignant tumors is under active investigation in sites such as breast, prostate, brain, liver, kidney, pancreas, and soft tissue. Hyperthermia therapy with MRgFUS is also feasible, and may be used in conjunction with radiotherapy and for local targeted drug delivery. MRI allows in situ target definition and provides continuous temperature monitoring and subsequent thermal dose mapping during HIFU. Although MRgHIFU can be very precise, treatment of mobile organs is challenging and advanced techniques are required because of artifacts in MR temperature mapping, the need for intercostal firing, and need for gated HIFU or tracking of the lesion in real time. The first invited talk, “MR guided Focused Ultrasound Treatment of Tumors in Bone and Soft Tissue”, will summarize the treatment protocol and review results from treatment of bone tumors. In addition, efforts to extend this technology to treat both benign and malignant soft tissue tumors of the extremities will be presented. The second invited talk, “MRI guided High Intensity Focused Ultrasound – Advanced Approaches for Ablation and Hyperthermia”, will provide an overview of techniques that are in or near clinical trials for thermal ablation and hyperthermia, with an emphasis of applications in abdominal organs and breast, including methods for MRTI and tracking targets in moving organs. Learning Objectives: Learn background on devices and techniques for MR guided HIFU for cancer therapy Understand issues and current status of clinical MRg HIFU Understand strategies for compensating for organ movement during MRgHIFU Understand strategies for strategies for delivering hyperthermia with MRgHIFU CM - research collaboration with Philips.

Gene therapy prospects--intranasal delivery of therapeutic genes.

Science.gov (United States)

Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

2012-01-01

Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

The ethics of gene therapy.

Science.gov (United States)

Chan, Sarah; Harris, John

2006-10-01

Recent developments have progressed in areas of science that pertain to gene therapy and its ethical implications. This review discusses the current state of therapeutic gene technologies, including stem cell therapies and genetic modification, and identifies ethical issues of concern in relation to the science of gene therapy and its application, including the ethics of embryonic stem cell research and therapeutic cloning, the risks associated with gene therapy, and the ethics of clinical research in developing new therapeutic technologies. Additionally, ethical issues relating to genetic modification itself are considered: the significance of the human genome, the distinction between therapy and enhancement, and concerns regarding gene therapy as a eugenic practice.

Gene therapy and reproductive medicine.

Science.gov (United States)

Stribley, John M; Rehman, Khurram S; Niu, Hairong; Christman, Gregory M

2002-04-01

To review the literature on the principles of gene therapy and its potential application in reproductive medicine. Literature review. Gene therapy involves transfer of genetic material to target cells using a delivery system, or vector. Attention has primarily focused on viral vectors. Significant problems remain to be overcome including low efficacy of gene transfer, the transient expression of some vectors, safety issues with modified adenoviruses and retroviruses, and ethical concerns. If these issues can be resolved, gene therapy will be applicable to an increasing spectrum of single and multiple gene disorders, as the Human Genome Project data are analyzed, and the genetic component of human disease becomes better understood. Gynecologic gene therapy has advanced to human clinical trials for ovarian carcinoma, and shows potential for the treatment of uterine leiomyomata. Obstetric applications of gene therapy, including fetal gene therapy, remain more distant goals. Concerns about the safety of human gene therapy research are being actively addressed, and remarkable progress in improving DNA transfer has been made. The first treatment success for a genetic disease (severe combined immunodeficiency disease) has been achieved, and ongoing research efforts will eventually yield clinical applications in many spheres of reproductive medicine.

The progress of tumor gene-radiotherapy induced by Egr-1 promoter

International Nuclear Information System (INIS)

Guo Rui; Li Biao

2010-01-01

The promoter of early growth response gene-1 (Egr-1) is a cis-acting element of Egr-1, and its activity is regulated by inducers such as ionizing radiation, free radical. In designated gene-radiotherapy system, radiation combined with therapeutic gene (such as tumor necrosis factor-α gene, suicide gene) can spatially and temporally regulate therapeutic gene expression in the irradiated field, produced a marked effect, while little systemic toxicities were observed. The combination of radiotherapy and gene therapy is promising in tumor therapy. (authors)

Gene therapy for ocular diseases.

Science.gov (United States)

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-05-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Intra-operative ultrasound hand-held strain imaging for the visualization of ablations produced in the liver with a toroidal HIFU transducer: first in vivo results

Energy Technology Data Exchange (ETDEWEB)

Chenot, J; Melodelima, D; N' Djin, W A; Souchon, Remi; Rivoire, M; Chapelon, J Y, E-mail: jeremy.chenot@inserm.f [Inserm, U556, Lyon, F-69003 (France)

2010-06-07

The use of hand-held ultrasound strain imaging for the intra-operative real-time visualization of HIFU (high-intensity focused ultrasound) ablations produced in the liver by a toroidal transducer was investigated. A linear 12 MHz ultrasound imaging probe was used to obtain radiofrequency signals. Using a fast cross-correlation algorithm, strain images were calculated and displayed at 60 frames s{sup -1}, allowing the use of hand-held strain imaging intra-operatively. Fourteen HIFU lesions were produced in four pigs. Intra-operative strain imaging of HIFU ablations in the liver was feasible owing to the high frame rate. The correlation between dimensions measured on gross pathology and dimensions measured on B-mode images and on strain images were R = 0.72 and R = 0.94 respectively. The contrast between ablated and non-ablated tissue was significantly higher (p < 0.05) in the strain images (22 dB) than in the B-mode images (9 dB). Strain images allowed equivalent or improved definition of ablated regions when compared with B-mode images. Real-time intra-operative hand-held strain imaging seems to be a promising complement to conventional B-mode imaging for the guidance of HIFU ablations produced in the liver during an open procedure. These results support that hand-held strain imaging outperforms conventional B-mode ultrasound and could potentially be used for the assessment of thermal therapies.

Study on radiation-inducible genes

Energy Technology Data Exchange (ETDEWEB)

Lim, Sang Yong; Kim, Dong Ho; Joe, Min Ho; Park, Hae Jun; Song, Hyu Npa

2012-01-15

Radiation-inducible genes of E. coli, which is a model strain for bacterial study, and Salmonella, which is a typical strain for pathogenic bacteria were compared through omic analysis. Heat shock response genes and prophage genes were induced by radiation in Salmonella, not in E. coli. Among prophage genes tested, STM2628 showed the highest activation by radiation, and approximately 1 kb promoter region was turned out to be necessary for radiation response. To screen an artificial promoter showing activation by 2 Gy, the high-throughput screening method using fluorescent MUG substrate was established. The use of bacteria as anticancer agents has attracted interest. In this study, we tried to develop tumor targeting bacteria in which the radiation-inducible promoter activate a transgene encoding a cytotoxic protein. To do this, a tumor-targeting hfq Salmonella mutant strain was constructed, and we found that its virulence decreased. For outward secretion of anticancer protein produced inside bacteria, the signal peptide of SspH1 was determined and the signal peptide was proven to be able to secrete an anticancer protein. Tumor xenograft mouse model was secured, which can be used for efficiency evaluation of bacterial tumor therapy.

Study on radiation-inducible genes

International Nuclear Information System (INIS)

Lim, Sang Yong; Kim, Dong Ho; Joe, Min Ho; Park, Hae Jun; Song, Hyu Npa

2012-01-01

Radiation-inducible genes of E. coli, which is a model strain for bacterial study, and Salmonella, which is a typical strain for pathogenic bacteria were compared through omic analysis. Heat shock response genes and prophage genes were induced by radiation in Salmonella, not in E. coli. Among prophage genes tested, STM2628 showed the highest activation by radiation, and approximately 1 kb promoter region was turned out to be necessary for radiation response. To screen an artificial promoter showing activation by 2 Gy, the high-throughput screening method using fluorescent MUG substrate was established. The use of bacteria as anticancer agents has attracted interest. In this study, we tried to develop tumor targeting bacteria in which the radiation-inducible promoter activate a transgene encoding a cytotoxic protein. To do this, a tumor-targeting hfq Salmonella mutant strain was constructed, and we found that its virulence decreased. For outward secretion of anticancer protein produced inside bacteria, the signal peptide of SspH1 was determined and the signal peptide was proven to be able to secrete an anticancer protein. Tumor xenograft mouse model was secured, which can be used for efficiency evaluation of bacterial tumor therapy

Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations

Directory of Open Access Journals (Sweden)

Seo-Young Lee

2016-01-01

Full Text Available The recent advent of induced pluripotent stem cells (iPSCs and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson’s disease, it has been well known that induced neural stem cells (iNSCs were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S. Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S, it would be ideal to simultaneously treat the LRRK2 (G2019S fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.

Human Gene Therapy: Genes without Frontiers?

Science.gov (United States)

Simon, Eric J.

2002-01-01

Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

Recent trends in the gene therapy of β-thalassemia

Directory of Open Access Journals (Sweden)

Finotti A

2015-02-01

Full Text Available Alessia Finotti,1–3 Laura Breda,4 Carsten W Lederer,6,7 Nicoletta Bianchi,1–3 Cristina Zuccato,1–3 Marina Kleanthous,6,7 Stefano Rivella,4,5 Roberto Gambari1–3 1Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy; 2Associazione Veneta per la Lotta alla Talassemia, Rovigo, Italy; 3Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy; 4Department of Pediatrics, Division of Haematology/Oncology, Weill Cornell Medical College, New York, NY, USA; 5Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY, USA; 6Department of Molecular Genetics Thalassaemia, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; 7Cyprus School of Molecular Medicine, Nicosia, Cyprus Abstract: The β-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult β-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for β-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from β-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most

Gene therapy of thyroid carcinoma

International Nuclear Information System (INIS)

Zheng Wei; Tan Jian

2007-01-01

Normally, differentiated thyroid carcinoma(DTC) is a disease of good prognosis, but about 30% of the tumors are dedifferentiate, which are inaccessible to standard therapeutic procedures such as 'operation, 131 I therapy and thyroid hormone'. Both internal and abroad experts are researching a new therapy of dedifferentiated thyroid carcinoma--gene therapy. Many of them utilize methods of it, but follow different strategies: (1) transduction of the thyroid sodium/iodide transporter gene to make tissues that do not accumulate iodide treatable by 131 I therapy; (2) strengthening of the anti-tumor immune response; (3) suicide gene therapy; (4) depression the generation of tumor cells; (5) gene therapy of anti- vascularization. (authors)

Targeting Herpetic Keratitis by Gene Therapy

Directory of Open Access Journals (Sweden)

Hossein Mostafa Elbadawy

2012-01-01

Full Text Available Ocular gene therapy is rapidly becoming a reality. By November 2012, approximately 28 clinical trials were approved to assess novel gene therapy agents. Viral infections such as herpetic keratitis caused by herpes simplex virus 1 (HSV-1 can cause serious complications that may lead to blindness. Recurrence of the disease is likely and cornea transplantation, therefore, might not be the ideal therapeutic solution. This paper will focus on the current situation of ocular gene therapy research against herpetic keratitis, including the use of viral and nonviral vectors, routes of delivery of therapeutic genes, new techniques, and key research strategies. Whereas the correction of inherited diseases was the initial goal of the field of gene therapy, here we discuss transgene expression, gene replacement, silencing, or clipping. Gene therapy of herpetic keratitis previously reported in the literature is screened emphasizing candidate gene therapy targets. Commonly adopted strategies are discussed to assess the relative advantages of the protective therapy using antiviral drugs and the common gene therapy against long-term HSV-1 ocular infections signs, inflammation and neovascularization. Successful gene therapy can provide innovative physiological and pharmaceutical solutions against herpetic keratitis.

High power phased array prototype for clinical high intensity focused ultrasound : applications to transcostal and transcranial therapy.

Science.gov (United States)

Pernot, M; Aubry, J -F; Tanter, M; Marquet, F; Montaldo, G; Boch, A -L; Kujas, M; Seilhean, D; Fink, M

2007-01-01

Bursts of focused ultrasound energy three orders of magnitude more intense than diagnostic ultrasound became during the last decade a noninvasive option for treating cancer from breast to prostate or uterine fibroid. However, many challenges remain to be addressed. First, the corrections of distortions induced on the ultrasonic therapy beam during its propagation through defocusing obstacles like skull bone or ribs remain today a technological performance that still need to be validated clinically. Secondly, the problem of motion artifacts particularly important for the treatment of abdominal parts becomes today an important research topic. Finally, the problem of the treatment monitoring is a wide subject of interest in the growing HIFU community. For all these issues, the potential of new ultrasonic therapy devices able to work both in Transmit and Receive modes will be emphasized. A review of the work under achievement at L.O.A. using this new generation of HIFU prototypes on the monitoring, motion correction and aberrations corrections will be presented.

Recent trends in the gene therapy of β-thalassemia

Science.gov (United States)

Finotti, Alessia; Breda, Laura; Lederer, Carsten W; Bianchi, Nicoletta; Zuccato, Cristina; Kleanthous, Marina; Rivella, Stefano; Gambari, Roberto

2015-01-01

The β-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult β-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for β-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from β-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in β-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for β-thalassemia model systems; for β-, γ-, and anti-sickling β-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of γ-globin and genome editing using designer nucleases. PMID:25737641

A Novel Combination of Thermal Ablation and Heat-Inducible Gene therapy for Breast Cancer Treatment

Science.gov (United States)

2009-04-01

11. Khokhlova, V.A., et al., Effects of nonlinear propagation, cavitation , and boiling in lesion formation by high intensity focused ultrasound in...intensity focused ultrasound (HIFU) has been developed as an emerging non-invasive strategy for cancer treatment by thermal ablation of tumor tissue. The...Concepts, Seattle, WA) operating at its fundamental frequency (1.1 MHz) or its third harmonics (3.3 MHz). The ultrasound imaging system was a 5/7

Gene therapy and radiotherapy in malignant tumor

International Nuclear Information System (INIS)

Zhang Yaowen; Cao Yongzhen; Li Jin; Wang Qin

2008-01-01

Tumor treatment is one of the most important fields in medical research. Nowadays, a novel method which is combined gene therapy with radiotherapy plays an important role in the field of cancer research, and mainly includes immune gene therapy combined with radiotherapy, suicide gene therapy or tumor suppressor gene therapy combined with radiotherapy, antiangiogenesis gene therapy combined with radiotherapy and protective gene therapy combined with radiotherapy based on the technical features. This review summarized the current status of combined therapies of gene therapy and radiotherapy and possible mechanism. (authors)

Gene Therapy and Children (For Parents)

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... Staying Safe Videos for Educators Search English Español Gene Therapy and Children KidsHealth / For Parents / Gene Therapy ... that don't respond to conventional therapies. About Genes Our genes help make us unique. Inherited from ...

American Society of Gene & Cell Therapy

Science.gov (United States)

... Gene & Cell Therapy Defined Gene therapy and cell therapy are overlapping fields of biomedical research that aim to repair the direct cause of genetic diseases. Read More Gene & Cell Therapy FAQ's Read the most common questions raised by ...

Approach of combined cancer gene therapy and radiation: response of promoters to ionizing radiation

International Nuclear Information System (INIS)

Anstett, A.

2005-09-01

Gene therapy is an emerging cancer treatment modality. We are interested in developing a radiation-inducible gene therapy system to sensitize the tumor vasculature to the effects of ionizing radiation (IR) treatment. An expression system based on irradiation-inducible promoters will drive the expression of anti-tumor genes in the tumor vasculature. Solid tumors are dependent on angio genesis, a process in which new blood vessels are formed from the pre-existing vasculature. Vascular endothelial cells are un transformed and genetically stable, thus avoiding the problem of resistance to the treatments. Vascular endothelial cells may therefore represent a suitable target for this therapeutic gene therapy strategy.The identification of IR-inducible promoters native to endothelial cells was performed by gene expression profiling using cDNA micro array technology. We describe the genes modified by clinically relevant doses of IR. The extension to high doses aimed at studying the effects of total radiation delivery to the tumor. The radio-inductiveness of the genes selected for promoter study was confirmed by RT-PCR. Analysis of the activity of promoters in response to IR was also assessed in a reporter plasmid. We found that authentic promoters cloned onto a plasmid are not suitable for cancer gene therapy due to their low induction after IR. In contrast, synthetic promoters containing repeated sequence-specific binding sites for IR-activated transcription factors such as NF-κB are potential candidates for gene therapy. The activity of five tandemly repeated TGGGGACTTTCCGC elements for NF-κB binding in a luciferase reporter was increased in a dose-dependent manner. Interestingly, the response to fractionated low doses was improved in comparison to the total single dose. Thus, we put present evidence that a synthetic promoter for NF-κB specific binding may have application in the radio-therapeutic treatment of cancer. (author)

Gene therapy: theoretical and bioethical concepts.

Science.gov (United States)

Smith, Kevin R

2003-01-01

Gene therapy holds great promise. Somatic gene therapy has the potential to treat a wide range of disorders, including inherited conditions, cancers, and infectious diseases. Early progress has already been made in the treatment of a range of disorders. Ethical issues surrounding somatic gene therapy are primarily those concerned with safety. Germline gene therapy is theoretically possible but raises serious ethical concerns concerning future generations.

Gene transfer therapy in vascular diseases.

Science.gov (United States)

McKay, M J; Gaballa, M A

2001-01-01

Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of

Effects of oxytocin on high intensity focused ultrasound (HIFU) ablation of adenomysis: A prospective study

International Nuclear Information System (INIS)

Zhang, Xin; Zou, Min; Zhang, Cai; He, Jia; Mao, Shihua; Wu, Qingrong; He, Min; Wang, Jian; Zhang, Ruitao; Zhang, Lian

2014-01-01

Objective: To investigate the effects of oxytocin on high-intensity focused ultrasound (HIFU) ablation for the treatment of adenomyosis. Materials and methods: Eighty-six patients with adenomyosis from three hospitals were randomly assigned to the oxytocin group or control group for HIFU treatment. During HIFU treatment, 80 units of oxytocin was added in 500 ml of 0.9% normal saline running at the rate of 2 ml/min (0.32 U/min) in the oxytocin group, while 0.9% normal saline was used in the control group. Both patients and HIFU operators were blinded to oxytocin or saline application. Treatment results, adverse effects were compared. Results: When using oxytocin, the non-perfused volume (NPV) ratio was 80.7 ± 11.6%, the energy-efficiency factor (EEF) was 8.1 ± 9.9 J/mm 3 , and the sonication time required to ablate 1 cm 3 was 30.0 ± 36.0 s/cm 3 . When not using oxytocin, the non-perfused volume ratio was 70.8 ± 16.7%, the EEF was 15.8 ± 19.6 J/mm 3 , and the sonication time required to ablate 1 cm 3 was 58.2 ± 72.7 S/cm 3 . Significant difference in the NPV ratio, EEF, and the sonication time required to ablate 1 cm 3 between the two groups was observed. No oxytocin related adverse effects occurred. Conclusion: Oxytocin could significantly decrease the energy for ablating adenomyosis with HIFU, safely enhance the treatment efficiency

Characterization of HIFU transducers designed for sonochemistry application: Acoustic streaming.

Science.gov (United States)

Hallez, L; Touyeras, F; Hihn, J-Y; Bailly, Y

2016-03-01

Cavitation distribution in a High Intensity Focused Ultrasound sonoreactors (HIFU) has been extensively described in the recent literature, including quantification by an optical method (Sonochemiluminescence SCL). The present paper provides complementary measurements through the study of acoustic streaming generated by the same kind of HIFU transducers. To this end, results of mass transfer measurements (electrodiffusional method) were compared to optical method ones (Particle Image Velocimetry). This last one was used in various configurations: with or without an electrode in the acoustic field in order to have the same perturbation of the wave propagation. Results show that the maximum velocity is not located at the focal but shifted near the transducer, and that this shift is greater for high powers. The two cavitation modes (stationary and moving bubbles) are greatly affect the hydrodynamic behavior of our sonoreactors: acoustic streaming and the fluid generated by bubble motion. The results obtained by electrochemical measurements show the same low hydrodynamic activity in the transducer vicinity, the same shift of the active focal toward the transducer, and the same absence of activity in the post-focal axial zone. The comparison with theoretical Eckart's velocities (acoustic streaming in non-cavitating media) confirms a very high activity at the "sonochemical focal", accounted for by wave distortion, which induced greater absorption coefficients. Moreover, the equivalent liquid velocities are one order of magnitude larger than the ones measured by PIV, confirming the enhancement of mass transfer by bubbles oscillation and collapse close to the surface, rather than from a pure streaming effect. Copyright © 2015 Elsevier B.V. All rights reserved.

Therapeutic genes for anti-HIV/AIDS gene therapy.

Science.gov (United States)

Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca

2013-01-01

The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.

Identification of Hematopoietic Stem Cell Engraftment Genes in Gene Therapy Studies.

Science.gov (United States)

Powers, John M; Trobridge, Grant D

2013-09-01

Hematopoietic stem cell (HSC) therapy using replication-incompetent retroviral vectors is a promising approach to provide life-long correction for genetic defects. HSC gene therapy clinical studies have resulted in functional cures for several diseases, but in some studies clonal expansion or leukemia has occurred. This is due to the dyregulation of endogenous host gene expression from vector provirus insertional mutagenesis. Insertional mutagenesis screens using replicating retroviruses have been used extensively to identify genes that influence oncogenesis. However, retroviral mutagenesis screens can also be used to determine the role of genes in biological processes such as stem cell engraftment. The aim of this review is to describe the potential for vector insertion site data from gene therapy studies to provide novel insights into mechanisms of HSC engraftment. In HSC gene therapy studies dysregulation of host genes by replication-incompetent vector proviruses may lead to enrichment of repopulating clones with vector integrants near genes that influence engraftment. Thus, data from HSC gene therapy studies can be used to identify novel candidate engraftment genes. As HSC gene therapy use continues to expand, the vector insertion site data collected will be of great interest to help identify novel engraftment genes and may ultimately lead to new therapies to improve engraftment.

HIFU Ultrasound Power Measurements at INRiM

International Nuclear Information System (INIS)

Durando, G; Guglielmone, C; Musacchio, C

2011-01-01

In this work the new system for the ultrasound power measurement of High Intensity Focused Ultrasound transducers realized at INRIM ultrasounds laboratory is presented. The system is based on a submersible load cell that takes the place of the balance. This solution presents essentially two advantages. The first one, of mechanical nature, is relevant to the fact that the target is directly connected to the force transducer, eliminating unwanted target motion at high power. The second, of electric nature, concerns the possibility to reduce the insonation time (the ON period of the electric driving signal to the HIFU transducer) under of 2 s, and is allowed for by the faster response of the force transducer (700 Hz bandwidth). The main components of uncertainty and the overall budget of the measurement system are presented together with the results of measures of conductance, G, carried on a HIFU transducer, at the work frequencies 2.0 MHz and 6.38 MHz, for values of power ranging from 10 W to 100 W. The results of the ultrasonic conductance, G, obtained with the new system are compared with values obtained using the traditional measuring system for low powers (P ≤ 20W).

Progress toward overcoming hypoxia-induced resistance to solid tumor therapy

International Nuclear Information System (INIS)

Karakashev, Sergey V; Reginato, Mauricio J

2015-01-01

Hypoxic tumors are associated with poor clinical outcome for multiple types of human cancer. This may be due, in part, to hypoxic cancer cells being resistant to anticancer therapy, including radiation therapy, chemotherapy, and targeted therapy. Hypoxia inducible factor 1, a major regulator of cellular response to hypoxia, regulates the expression of genes that are involved in multiple aspects of cancer biology, including cell survival, proliferation, metabolism, invasion, and angiogenesis. Here, we review multiple pathways regulated by hypoxia/hypoxia inducible factor 1 in cancer cells and discuss the latest advancements in overcoming hypoxia-mediated tumor resistance

Enhanced efficacy of radiation-induced gene therapy in mice bearing lung adenocarcinoma xenografts using hypoxia responsive elements

International Nuclear Information System (INIS)

Wang Wei-dong; Chen Zheng-tang; Li De-zhi; Duan Yu-zhong; Cao Zheng-huai; Li Rong

2005-01-01

The aim of the present study was to investigate whether the hypoxia responsive element (HRE) could be used to enhance suicide gene (HSV-tk) expression and tumoricidal activity in radiation-controlled gene therapy of human lung adenocarcinoma xenografts. A chimeric promoter, HRE-Egr, was generated by directly linking a 0.3-kb fragment of HRE to a 0.6-kb human Egr-1 promoter. Retroviral vectors containing luciferase or the HSV-tk gene driven by Egr-1 or HRE-Egr were constructed. A human adenocarcinoma cell line (A549) was stably transfected with the above vectors using the lipofectamine method. The sensitivity of transfected cells to prodrug ganciclovir (GCV) and cell survival rates were analyzed after exposure to a dose of 2 Gy radiation and hypoxia (1%). In vivo, tumor xenografts in BALB/c mice were transfected with the constructed retroviruses and irradiated to a total dose of 6 Gy, followed by GCV treatment (20 mg/kg for 14 days). When the HSV-tk gene controlled by the HRE-Egr promoter was introduced into A549 cells by a retroviral vector, the exposure to 1% O 2 and 2 Gy radiation induced significant enhancement of GCV cytotoxicity to the cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors infected with the hybrid promoter-containing virus gradually disappeared after GCV administration and radiation. These results indicate that HRE can enhance transgene expression and tumoricidal activity in HSV-tk gene therapy controlled by ionizing radiation in hypoxic human lung adenocarcinoma. (author)

Gene transfer technology and genetic radioisotope targeting therapy

International Nuclear Information System (INIS)

Wang Jiaqiong; Wang Zizheng

2004-01-01

With deeper cognition about mechanisms of disease at the cellular and molecular level, gene therapy has become one of the most important research fields in medical molecular biology at present. Gene transfer technology plays an important role during the course of gene therapy, and further improvement should be made about vectors carrying target gene sequences. Also, gene survey is needed during gene therapy, and gene imaging is the most effective method. The combination of gene therapy and targeted radiotherapy, that is, 'Genetic Radioisotope Targeting Therapy', will be a novel approach to tumor gene therapy

Development of a high-field MR-guided HIFU setup for thermal and mechanical ablation methods in small animals

NARCIS (Netherlands)

Hoogenboom, M.; Amerongen, M.J. van; Eikelenboom, D.C.; Wassink, M.; Brok, M.H. den; Hulsbergen-van de Kaa, C.A.; Dumont, E.; Adema, G.J.; Heerschap, A.; Futterer, J.J.

2015-01-01

BACKGROUND: Thermal and mechanical high intensity focused ultrasound (HIFU) ablation techniques are in development for non-invasive treatment of cancer. However, knowledge of in vivo histopathologic and immunologic reactions after HIFU ablation is still limited. This study aims to create a setup for

Gene Therapy of T Helper Cells in HIV Infection. Mathematical Model of the Criteria for Clinical Effect

DEFF Research Database (Denmark)

Lund, Ole; Lund, Ole søgaard; Gram, Gregers

1997-01-01

The paper presents a mathematical model of the criteria for gene therapy of T helper cells to have a clinical effect on HIV infection. Our main results are that the therapy should be designed to give the transduced cells a significant but not necessarily total protection against HIV-induced cell...... deaths, and to avoid the production of viral mutants that are insensitive to gene therapy. The transduced cells will not survive if the gene therapy only blocks the spread of virus....

Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

Directory of Open Access Journals (Sweden)

Zhang Kang-Jian

2012-02-01

Full Text Available Abstract Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.

Strategies in Gene Therapy for Glioblastoma

International Nuclear Information System (INIS)

Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S.

2013-01-01

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy

Strategies in Gene Therapy for Glioblastoma

Energy Technology Data Exchange (ETDEWEB)

Kwiatkowska, Aneta; Nandhu, Mohan S.; Behera, Prajna; Chiocca, E. Antonio; Viapiano, Mariano S., E-mail: mviapiano@partners.org [Department of Neurosurgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 (United States)

2013-10-22

Glioblastoma (GBM) is the most aggressive form of brain cancer, with a dismal prognosis and extremely low percentage of survivors. Novel therapies are in dire need to improve the clinical management of these tumors and extend patient survival. Genetic therapies for GBM have been postulated and attempted for the past twenty years, with variable degrees of success in pre-clinical models and clinical trials. Here we review the most common approaches to treat GBM by gene therapy, including strategies to deliver tumor-suppressor genes, suicide genes, immunomodulatory cytokines to improve immune response, and conditionally-replicating oncolytic viruses. The review focuses on the strategies used for gene delivery, including the most common and widely used vehicles (i.e., replicating and non-replicating viruses) as well as novel therapeutic approaches such as stem cell-mediated therapy and nanotechnologies used for gene delivery. We present an overview of these strategies, their targets, different advantages, and challenges for success. Finally, we discuss the potential of gene therapy-based strategies to effectively attack such a complex genetic target as GBM, alone or in combination with conventional therapy.

Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy.

Science.gov (United States)

Bakhtiar, Athirah; Sayyad, Mustak; Rosli, Rozita; Maruyama, Atsushi; Chowdhury, Ezharul H

2014-01-01

Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors.

Endocrine aspects of cancer gene therapy.

Science.gov (United States)

Barzon, Luisa; Boscaro, Marco; Palù, Giorgio

2004-02-01

The field of cancer gene therapy is in continuous expansion, and technology is quickly moving ahead as far as gene targeting and regulation of gene expression are concerned. This review focuses on the endocrine aspects of gene therapy, including the possibility to exploit hormone and hormone receptor functions for regulating therapeutic gene expression, the use of endocrine-specific genes as new therapeutic tools, the effects of viral vector delivery and transgene expression on the endocrine system, and the endocrine response to viral vector delivery. Present ethical concerns of gene therapy and the risk of germ cell transduction are also discussed, along with potential lines of innovation to improve cell and gene targeting.

In vivo photoacoustics and high frequency ultrasound imaging of mechanical high intensity focused ultrasound (HIFU) ablation.

Science.gov (United States)

Daoudi, Khalid; Hoogenboom, Martijn; den Brok, Martijn; Eikelenboom, Dylan; Adema, Gosse J; Fütterer, Jürgen J; de Korte, Chris L

2017-04-01

The thermal effect of high intensity focused ultrasound (HIFU) has been clinically exploited over a decade, while the mechanical HIFU is still largely confined to laboratory investigations. This is in part due to the lack of adequate imaging techniques to better understand the in-vivo pathological and immunological effects caused by the mechanical treatment. In this work, we explore the use of high frequency ultrasound (US) and photoacoustics (PA) as a potential tool to evaluate the effect of mechanical ablation in-vivo , e.g. boiling histotripsy. Two mice bearing a neuroblastoma tumor in the right leg were ablated using an MRI-HIFU system conceived for small animals and monitored using MRI thermometry. High frequency US and PA imaging were performed before and after the HIFU treatment. Afterwards, the tumor was resected for further assessment and evaluation of the ablated region using histopathology. High frequency US imaging revealed the presence of liquefied regions in the treated area together with fragmentized tissue which appeared with different reflecting proprieties compared to the surrounding tissue. Photoacoustic imaging on the other hand revealed the presence of deoxygenated blood within the tumor after the ablation due to the destruction of blood vessel network while color Doppler imaging confirmed the blood vessel network destruction within the tumor. The treated area and the presence of red blood cells detected by photoacoustics were further confirmed by the histopathology. This feasibility study demonstrates the potential of high frequency US and PA approach for assessing in-vivo the effect of mechanical HIFU tumor ablation.

Targeted cancer gene therapy : the flexibility of adenoviral gene therapy vectors

NARCIS (Netherlands)

Rots, MG; Curiel, DT; Gerritsen, WR; Haisma, HJ

2003-01-01

Recombinant adenoviral vectors are promising reagents for therapeutic interventions in humans, including gene therapy for biologically complex diseases like cancer and cardiovascular diseases. In this regard, the major advantage of adenoviral vectors is their superior in vivo gene transfer

Republished review: Gene therapy for ocular diseases.

Science.gov (United States)

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-07-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

HIFU e nanobolle di ossigeno: due differenti approcci per il trattamento del cancro - HIFU and oxygen load nanobubbles:two different approches for cancer treatment

Directory of Open Access Journals (Sweden)

Chiara Magnetto

2015-07-01

Full Text Available L’utilizzo di ultrasuoni focalizzati ad alta intensità (HIFU ha ottenuto un rapido consenso in ambito clinico come strumento chirurgico non invasivo per l’ablazione di cellule tumorali. L’impiego di tale tecnologia, applicata simultaneamente a nano-bolle riempite di ossigeno (OLN, realizzate e caratterizzate presso l’INRiM e volte a trattare patologie associate all’ipossia (come i tumori, costituiscono un innovativo strumento terapeutico per la cura del cancro proposto in questo lavoro. ---------- Use of high intensity focused ultrasound (HIFU beam has gained rapid agreement in clinical environment as a tool for non-invasive surgical ablation of tumor cells. This technology, applied simultaneously to nano-bubbles filled with oxygen (OLN, realized and characterized at INRiM with the purpose of treating diseases associated to hypoxia (such as tumors, constitute an innovative therapeutic tool for cancer treatment proposed in this article.

Progress in Gene Therapy for Prostate Cancer

International Nuclear Information System (INIS)

Ahmed, Kamran A.; Davis, Brian J.; Wilson, Torrence M.; Wiseman, Gregory A.; Federspiel, Mark J.; Morris, John C.

2012-01-01

Gene therapy has held promise to correct various disease processes. Prostate cancer represents the second leading cause of cancer death in American men. A number of clinical trials involving gene therapy for the treatment of prostate cancer have been reported. The ability to efficiently transduce tumors with effective levels of therapeutic genes has been identified as a fundamental barrier to effective cancer gene therapy. The approach utilizing gene therapy in prostate cancer patients at our institution attempts to address this deficiency. The sodium-iodide symporter (NIS) is responsible for the ability of the thyroid gland to transport and concentrate iodide. The characteristics of the NIS gene suggest that it could represent an ideal therapeutic gene for cancer therapy. Published results from Mayo Clinic researchers have indicated several important successes with the use of the NIS gene and prostate gene therapy. Studies have demonstrated that transfer of the human NIS gene into prostate cancer using adenovirus vectors in vitro and in vivo results in efficient uptake of radioactive iodine and significant tumor growth delay with prolongation of survival. Preclinical successes have culminated in the opening of a phase I trial for patients with advanced prostate disease which is currently accruing patients. Further study will reveal the clinical promise of NIS gene therapy in the treatment of prostate as well as other malignancies.

Progress in Gene Therapy for Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Ahmed, Kamran A.; Davis, Brian J. [Department of Radiation Oncology, Mayo Clinic, Rochester, MN (United States); Wilson, Torrence M. [Department of Urology, Mayo Clinic, Rochester, MN (United States); Wiseman, Gregory A. [Division of Nuclear Medicine, Mayo Clinic, Rochester, MN (United States); Federspiel, Mark J. [Department of Molecular Medicine, Mayo Clinic, Rochester, MN (United States); Morris, John C., E-mail: davis.brian@mayo.edu [Division of Endocrinology, Mayo Clinic, Rochester, MN (United States)

2012-11-19

Gene therapy has held promise to correct various disease processes. Prostate cancer represents the second leading cause of cancer death in American men. A number of clinical trials involving gene therapy for the treatment of prostate cancer have been reported. The ability to efficiently transduce tumors with effective levels of therapeutic genes has been identified as a fundamental barrier to effective cancer gene therapy. The approach utilizing gene therapy in prostate cancer patients at our institution attempts to address this deficiency. The sodium-iodide symporter (NIS) is responsible for the ability of the thyroid gland to transport and concentrate iodide. The characteristics of the NIS gene suggest that it could represent an ideal therapeutic gene for cancer therapy. Published results from Mayo Clinic researchers have indicated several important successes with the use of the NIS gene and prostate gene therapy. Studies have demonstrated that transfer of the human NIS gene into prostate cancer using adenovirus vectors in vitro and in vivo results in efficient uptake of radioactive iodine and significant tumor growth delay with prolongation of survival. Preclinical successes have culminated in the opening of a phase I trial for patients with advanced prostate disease which is currently accruing patients. Further study will reveal the clinical promise of NIS gene therapy in the treatment of prostate as well as other malignancies.

SU-F-J-215: Non-Thermal Pulsed High Intensity Focused Ultrasound Therapy Combined with 5-Aminolevulinic Acid: An in Vivo Pilot Study

Energy Technology Data Exchange (ETDEWEB)

Wang, B; He, W; Cvetkovic, D; Chen, L; Ma, C [Fox Chase Cancer Center, Philadelphia, PA (United States)

2016-06-15

Purpose: It has recently been shown that non-thermal pulsed high intensity focused ultrasound (pHIFU) has a cell-killing effect. The purpose of the study is to investigate the sonosensitizing effect of 5-Aminolevulinic Acid (5-ALA) in non-thermal pHIFU cancer therapy. Methods: FaDu human head and neck squamous cell carcinoma cells were injected subcutaneously in the flanks of nude mice. After one to two weeks, the tumors reached the volume of 112 ± 8 mm3 and were assigned randomly into a non-thermal pHIFU group (n=9) and a non-thermal sonodynamic therapy (pHIFU after 5-ALA administration) group (n=7). The pHIFU treatments (parameters: 1 MHz frequency; 25 W acoustic power; 0.1 duty cycle; 60 seconds duration) were delivered using an InSightec ExAblate 2000 system with a GE Signa 1.5T MR scanner. The mice in the non-thermal sonodynamic group received 5-ALA tail-vein injection 4 hours prior to the pHIFU treatment. The tumor growth was monitored using the CT scanner on a Sofie-Biosciences G8 PET/CT system. Results: The tumors in this study grew very aggressively and about 60% of the tumors in this study developed ulcerations at various stages. Tumor growth delay after treatments was observed by comparing the treated (n=9 in pHIFU group; n=7 in sonodynamic group) and untreated tumors (n=17). However, no statistically significant differences were found between the non-thermal pHIFU and non-thermal sonodynamic group. The mean normalized tumor volume of the untreated tumors on Day 7 after their first CT scans was 7.05 ± 0.54, while the normalized volume of the treated tumors on Day 7 after treatment was 5.89 ± 0.79 and 6.27 ± 0.47 for the sonodynamic group and pHIFU group, respectively. Conclusion: In this study, no significant sonosensitizing effects of 5-ALA were obtained on aggressive FaDu tumors despite apparent tumor growth delay in some mice treated with non-thermal sonodynamic therapy.

Gene therapy for prostate cancer.

LENUS (Irish Health Repository)

Tangney, Mark

2012-01-31

Cancer remains a leading cause of morbidity and mortality. Despite advances in understanding, detection, and treatment, it accounts for almost one-fourth of all deaths per year in Western countries. Prostate cancer is currently the most commonly diagnosed noncutaneous cancer in men in Europe and the United States, accounting for 15% of all cancers in men. As life expectancy of individuals increases, it is expected that there will also be an increase in the incidence and mortality of prostate cancer. Prostate cancer may be inoperable at initial presentation, unresponsive to chemotherapy and radiotherapy, or recur following appropriate treatment. At the time of presentation, patients may already have metastases in their tissues. Preventing tumor recurrence requires systemic therapy; however, current modalities are limited by toxicity or lack of efficacy. For patients with such metastatic cancers, the development of alternative therapies is essential. Gene therapy is a realistic prospect for the treatment of prostate and other cancers, and involves the delivery of genetic information to the patient to facilitate the production of therapeutic proteins. Therapeutics can act directly (eg, by inducing tumor cells to produce cytotoxic agents) or indirectly by upregulating the immune system to efficiently target tumor cells or by destroying the tumor\\'s vasculature. However, technological difficulties must be addressed before an efficient and safe gene medicine is achieved (primarily by developing a means of delivering genes to the target cells or tissue safely and efficiently). A wealth of research has been carried out over the past 20 years, involving various strategies for the treatment of prostate cancer at preclinical and clinical trial levels. The therapeutic efficacy observed with many of these approaches in patients indicates that these treatment modalities will serve as an important component of urological malignancy treatment in the clinic, either in isolation or

Leber’s congenital amaurosis and the role of gene therapy in congenital retinal disorders

Directory of Open Access Journals (Sweden)

Walid Sharif

2017-03-01

Full Text Available Leber’s congenital amaurosis (LCA and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE, PubMed and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium (RPE derived retinoid isomerohydrolase (RPE65 to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine, porcine and rodent LCA2 models. The recombinant AAV2.hRPE65v2 adeno-associated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively, could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful, it will lead the way to additional gene therapy attempts to cure monogenic, inherited retinopathies.

Leber’s congenital amaurosis and the role of gene therapy in congenital retinal disorders

Institute of Scientific and Technical Information of China (English)

Walid; Sharif; Zuhair; Sharif

2017-01-01

Leber’s congenital amaurosis(LCA)and recent gene therapy advancement for treating inherited retinopathies were extensive literature reviewed using MEDLINE,Pub Med and EMBASE. Adeno-associated viral vectors were the most utilised vectors for ocular gene therapy. Cone photoreceptor cells might use an alternate pathway which was not reliant of the retinal pigment epithelium(RPE)derived retinoid isomerohydrolase(RPE65)to access the 11-cis retinal dehydechromophore. Research efforts dedicated on the progression of a gene-based therapy for the treatment of LCA2. Such gene therapy approaches were extremely successful in canine,porcine and rodent LCA2 models. The recombinant AAV2.h RPE65v2 adenoassociated vector contained the RPE65 cDNA and was replication deficient. Its in vitro injection in target cells induced RPE65 protein production. The gene therapy trials that were so far conducted for inherited retinopathies have generated promising results. Phase I clinical trials to cure LCA and choroideremia demonstrated that adeno-associated viral vectors containing RPE genes and photoreceptors respectively,could be successfully administered to inherited retinopathy patients. A phase III trial is presently ongoing and if successful,it will lead the way to additional gene therapy attempts to cure monogenic,inherited retinopathies.

Human gene therapy and imaging: cardiology

International Nuclear Information System (INIS)

Wu, Joseph C.; Yla-Herttuala, Seppo

2005-01-01

This review discusses the basics of cardiovascular gene therapy, the results of recent human clinical trials, and the rapid progress in imaging techniques in cardiology. Improved understanding of the molecular and genetic basis of coronary heart disease has made gene therapy a potential new alternative for the treatment of cardiovascular diseases. Experimental studies have established the proof-of-principle that gene transfer to the cardiovascular system can achieve therapeutic effects. First human clinical trials provided initial evidence of feasibility and safety of cardiovascular gene therapy. However, phase II/III clinical trials have so far been rather disappointing and one of the major problems in cardiovascular gene therapy has been the inability to verify gene expression in the target tissue. New imaging techniques could significantly contribute to the development of better gene therapeutic approaches. Although the exact choice of imaging modality will depend on the biological question asked, further improvement in image resolution and detection sensitivity will be needed for all modalities as we move from imaging of organs and tissues to imaging of cells and genes. (orig.)

Respiratory-Gated MRgHIFU in Upper Abdomen Using an MR-Compatible In-Bore Digital Camera

Directory of Open Access Journals (Sweden)

Vincent Auboiroux

2014-01-01

Full Text Available Objective. To demonstrate the technical feasibility and the potential interest of using a digital optical camera inside the MR magnet bore for monitoring the breathing cycle and subsequently gating the PRFS MR thermometry, MR-ARFI measurement, and MRgHIFU sonication in the upper abdomen. Materials and Methods. A digital camera was reengineered to remove its magnetic parts and was further equipped with a 7 m long USB cable. The system was electromagnetically shielded and operated inside the bore of a closed 3T clinical scanner. Suitable triggers were generated based on real-time motion analysis of the images produced by the camera (resolution 640×480 pixels, 30 fps. Respiratory-gated MR-ARFI prepared MRgHIFU ablation was performed in the kidney and liver of two sheep in vivo, under general anaesthesia and ventilator-driven forced breathing. Results. The optical device demonstrated very good MR compatibility. The current setup permitted the acquisition of motion artefact-free and high resolution MR 2D ARFI and multiplanar interleaved PRFS thermometry (average SNR 30 in liver and 56 in kidney. Microscopic histology indicated precise focal lesions with sharply delineated margins following the respiratory-gated HIFU sonications. Conclusion. The proof-of-concept for respiratory motion management in MRgHIFU using an in-bore digital camera has been validated in vivo.

Gene therapy and its implications in Periodontics

Science.gov (United States)

Mahale, Swapna; Dani, Nitin; Ansari, Shumaila S.; Kale, Triveni

2009-01-01

Gene therapy is a field of Biomedicine. With the advent of gene therapy in dentistry, significant progress has been made in the control of periodontal diseases and reconstruction of dento-alveolar apparatus. Implementation in periodontics include: -As a mode of tissue engineering with three approaches: cell, protein-based and gene delivery approach. -Genetic approach to Biofilm Antibiotic Resistance. Future strategies of gene therapy in preventing periodontal diseases: -Enhances host defense mechanism against infection by transfecting host cells with an antimicrobial peptide protein-encoding gene. -Periodontal vaccination. Gene therapy is one of the recent entrants and its applications in the field of periodontics are reviewed in general here. PMID:20376232

Gene Therapy for Parkinson's Disease

Directory of Open Access Journals (Sweden)

Rachel Denyer

2012-01-01

Full Text Available Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field.

Development of a High Intensity Focused Ultrasound (HIFU) Hydrophone System

International Nuclear Information System (INIS)

Schafer, Mark E.; Gessert, James

2009-01-01

The growing clinical use of High Intensity Focused Ultrasound (HIFU) has driven a need for reliable, reproducible measurements of HIFU acoustic fields. We have previously presented data on a reflective scatterer approach, incorporating several novel features for improved bandwidth, reliability, and reproducibility [Proc. 2005 IEEE Ultrasonics Symposium, 1739-1742]. We now report on several design improvements which have increase the signal to noise ratio of the system, and potentially reduced the cost of implementation. For the scattering element, we now use an artificial sapphire material to provide a more uniform radiating surface. The receiver is a segmented, truncated spherical structure with a 10 cm radius; the scattering element is positioned at the center of the sphere. The receiver is made from 25 micron thick, biaxially stretched PVDF, with a Pt-Au electrode on the front surface. In the new design, a specialized backing material provides the stiffness required to maintain structural stability, while at the same time providing both electrical shielding and ultrasonic absorption. Compared with the previous version, the new receiver design has improved the noise performance by 8-12 dB; the new scattering sphere has reduced the scattering loss by another 14 dB, producing an effective sensitivity of -298 dB re 1 microVolt/Pa. The design trade-off still involves receiver sensitivity with effective spot size, and signal distortion from the scatter structure. However, the reduced cost and improved repeatability of the new scatter approach makes the overall design more robust for routine waveform measurements of HIFU systems.

Tissue specific promoters improve the localization of radiation-inducible gene expression

International Nuclear Information System (INIS)

Hallahan, Dennis; Kataoka, Yasushi; Kuchibhotla, Jaya; Virudachalam, Subbu; Weichselbaum, Ralph

1996-01-01

Purpose: Site-specific activation of gene expression can be achieved by the use of a promoter that is induced by physical agents such as x-rays. The purpose of the present study was to determine whether site-specific activation of gene therapy can also be achieved within the vascular endothelium by use of radiation-inducible promoters. We studied induction of promoter-reporter gene constructs using previously identified radiation-promoters from c-jun, c-fos, Egr-1, ICAM-1, ELAM-1 after transfection into in the vascular endothelium. Methods: The following radiation-inducible genetic constructs were created: The ELAM-1 promoter fragment was cloned into pOGH to obtain the pE-sel(-587 +35)GH reporter construct. The ICAM-1 promoter fragment (-1162/+1) was cloned upstream of the CAT coding region of the pCAT-plasmid (Promega) after removal of the SV40 promoter by Bgl2/Stu1 digestion to create the pBS-CAT plasmid. The 132 to +170 bp segment of the 5' untranslated region of the c-jun promoter was cloned to the CAT reporter gene to create the -132/+170 cjun-CAT. The Egr-1 promoter fragment (-425/+75) was cloned upstream of the CAT coding region to create the pE425-CAT plasmid. Tandem repeats of the AP-1 binding site were cloned upstream of the CAT coding region (3 xTRE-CAT). Tandem repeats of the Egr binding site (EBS) were cloned upstream of the CAT coding region (EBS-CAT). Human vascular endothelial cells from both large vessel and small vessel origin (HUVEC and HMEC), as well as human tumor cell lines were transfected with plasmids -132/+170 cjun-CAT, pE425-CAT, 3 xTRE-CAT, EBS-CAT, pE-sel-GH and pBS-CAT by use of liposomes. Humor tumor cell lines included SQ20B (squamous), RIT3 (sarcoma), and HL525 (leukemia). Each plasmid was cotransfected with a plasmid containing a CMV promoter linked to the LacZ gene (1 μg). Transfected cells were treated with mock irradiation or x-rays. Cell extracts were assayed for reporter gene expression. Results: Radiation-induced gene

Gene therapy for lipid disorders

Directory of Open Access Journals (Sweden)

Rader Daniel J

2000-10-01

Full Text Available Abstract Lipid disorders are associated with atherosclerotic vascular disease, and therapy is associated with a substantial reduction in cardiovascular events. Current approaches to the treatment of lipid disorders are ineffective in a substantial number of patients. New therapies for refractory hypercholesterolemia, severe hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol are needed: somatic gene therapy is one viable approach. The molecular etiology and pathophysiology of most of the candidate diseases are well understood. Animal models exist for the diseases and in many cases preclinical proof-of-principle studies have already been performed. There has been progress in the development of vectors that provide long-term gene expression. New clinical gene therapy trials for lipid disorders are likely to be initiated within the next few years.

Porcine pilot study of MRI-guided HIFU treatment for neonatal intraventricular hemorrhage (IVH)

Science.gov (United States)

Looi, Thomas; Waspe, Adam; Mougenot, Charles; Amaral, Joao; Temple, Michael; Hynynen, Kullervo; Drake, James

2012-11-01

Intraventricular hemorrhage (IVH) occurs in 15% of premature babies and 50% of IVH cases progress to posthemorrhagic ventricular dilation due to large blood clots forming in the ventricles. Existing treatments such as tissue plasminogen activator (tPA) and surgical intervention have severe side effects in paediatric patients that include excessive bleeding and complications. This study investigates the feasibility of MR-HIFU for sonothrombolysis of blood clots from IVH using natural acoustic windows, known as fontanelles, in the skulls of newborns. The study involved 2 elements: a phantom study to examine beam limitations and acoustic properties, and an in-vivo porcine study. A phantom skull was created from sample patient data and was used to analyze reachability of the Philips Sonavelle system. Acoustic measurements of the phantom (attenuation of 5-14 dB and speed of sound of 1722-2965 m/s) indicated the phantom effectively mimics neonatal skull bone. For the ex-vivo studies, a porcine clot was created and sonicated for 5 mins at 500W with a 0.5% duty cycle. For the in-vivo experiment, a vertex craniotomy was performed and porcine blood was injected into the lateral ventricle under ultrasound guidance. Sonication using the prior parameters induced cavitation and post-sonication T1 and T2 images verified clot lysis. Further H&E analysis showed no presence of blood in the ventricles. These positive results show that MR-HIFU has potential as a noninvasive tool for sonothrombolysis of neonatal IVH clots.

Cavitation-enhanced MR-guided focused ultrasound ablation of rabbit tumors in vivo using phase shift nanoemulsions

International Nuclear Information System (INIS)

Kopechek, Jonathan A; Porter, Tyrone M; Park, Eun-Joo; Zhang, Yong-Zhi; Vykhodtseva, Natalia I; McDannold, Nathan J

2014-01-01

Advanced tumors are often inoperable due to their size and proximity to critical vascular structures. High intensity focused ultrasound (HIFU) has been developed to non-invasively thermally ablate inoperable solid tumors. However, the clinical feasibility of HIFU ablation therapy has been limited by the long treatment times (on the order of hours) and high acoustic intensities required. Studies have shown that inertial cavitation can enhance HIFU-mediated heating by generating broadband acoustic emissions that increase tissue absorption and accelerate HIFU-induced heating. Unfortunately, initiating inertial cavitation in tumors requires high intensities and can be unpredictable. To address this need, phase-shift nanoemulsions (PSNE) have been developed. PSNE consist of lipid-coated liquid perfluorocarbon droplets that are less than 200 nm in diameter, thereby allowing passive accumulation in tumors through leaky tumor vasculature. PSNE can be vaporized into microbubbles in tumors in order to nucleate cavitation activity and enhance HIFU-mediated heating. In this study, MR-guided HIFU treatments were performed on intramuscular rabbit VX2 tumors in vivo to assess the effect of vaporized PSNE on acoustic cavitation and HIFU-mediated heating. HIFU pulses were delivered for 30 s using a 1.5 MHz, MR-compatible transducer, and cavitation emissions were recorded with a 650 kHz ring hydrophone while temperature was monitored using MR thermometry. Cavitation emissions were significantly higher (P < 0.05) after PSNE injection and this was well correlated with enhanced HIFU-mediated heating in tumors. The peak temperature rise induced by sonication was significantly higher (P < 0.05) after PSNE injection. For example, the mean per cent change in temperature achieved at 5.2 W of acoustic power was 46 ± 22% with PSNE injection. The results indicate that PSNE nucleates cavitation which correlates with enhanced HIFU-mediated heating in tumors. This suggests that PSNE could

Screening of microbial radiation-inducible promoter and study of its expression; Development of basic technique of radiogenic therapy

Energy Technology Data Exchange (ETDEWEB)

Lim, Sangyong; Kim Dongho; Yang, Jaeseung

2007-02-15

In the search for new therapeutic modalities for cancer, gene therapy has attracted enormous interest over the last few years. Recently, the use of bacteria as a tumor specific protein transfer system has attracted interest. Attenuated Salmonella has been shown to provide selective colonization in tumors. This strategy to apply gene therapy for cancer has been defined as 'Radiogenic Therapy'. In this research, firstly, we screened a radiation inducible promoter of Salmonella responding to clinically relevant low dose of 10 Gy using microarray analysis. Of all genes showing a expression ratio of at least 2-fold changes relative to wild type, 168 genes were induced. To confirm the findings of the microarray by an alternative method, we investigated the transcriptional changes of radio-inducible genes using real time PCR analysis. To verify the ability of screened genes (fadB, narK, cyoA, STM1011, STM2617, and STM2632) to produce a downstream protein by irradiation, the reporter plasmids were constructed. Finally, we found that the promoter of fadB, cyoA, and STM2617 can be activated by irradiation within cancer cells. These results suggest that these genes may be the most probable candidate used in radiogenic therapy.

Screening of microbial radiation-inducible promoter and study of its expression; Development of basic technique of radiogenic therapy

International Nuclear Information System (INIS)

Lim, Sangyong; Kim Dongho; Yang, Jaeseung

2007-02-01

In the search for new therapeutic modalities for cancer, gene therapy has attracted enormous interest over the last few years. Recently, the use of bacteria as a tumor specific protein transfer system has attracted interest. Attenuated Salmonella has been shown to provide selective colonization in tumors. This strategy to apply gene therapy for cancer has been defined as 'Radiogenic Therapy'. In this research, firstly, we screened a radiation inducible promoter of Salmonella responding to clinically relevant low dose of 10 Gy using microarray analysis. Of all genes showing a expression ratio of at least 2-fold changes relative to wild type, 168 genes were induced. To confirm the findings of the microarray by an alternative method, we investigated the transcriptional changes of radio-inducible genes using real time PCR analysis. To verify the ability of screened genes (fadB, narK, cyoA, STM1011, STM2617, and STM2632) to produce a downstream protein by irradiation, the reporter plasmids were constructed. Finally, we found that the promoter of fadB, cyoA, and STM2617 can be activated by irradiation within cancer cells. These results suggest that these genes may be the most probable candidate used in radiogenic therapy

Gene therapy in periodontics.

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Chatterjee, Anirban; Singh, Nidhi; Saluja, Mini

2013-03-01

GENES are made of DNA - the code of life. They are made up of two types of base pair from different number of hydrogen bonds AT, GC which can be turned into instruction. Everyone inherits genes from their parents and passes them on in turn to their children. Every person's genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases. Gene therapy is 'the use of genes as medicine'. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual in order to repair a faulty gene copy. Thus it may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. It has a promising era in the field of periodontics. Gene therapy has been used as a mode of tissue engineering in periodontics. The tissue engineering approach reconstructs the natural target tissue by combining four elements namely: Scaffold, signaling molecules, cells and blood supply and thus can help in the reconstruction of damaged periodontium including cementum, gingival, periodontal ligament and bone.

Ovarian cancer targeted adenoviral-mediated mda-7/IL-24 gene therapy

NARCIS (Netherlands)

Mahasreshti, PJ; Kataram, M; Wu, HJ; Yalavarthy, LP; Carey, D; Dent, P; Chada, S; Alvarez, RD; Haisma, HJ; Fisher, PB; Curiel, DT

Objective. We have previously shown that adenoviral-mediated melanoma differentiation-associated gene-7 (Ad.mda-7) therapy induces apoptosis in ovarian cancer cells. However, the apoptosis induction was low and directly correlated with infectivity of Ad.mda-7. The objective of this study was to

Cancer suicide gene therapy: a patent review.

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Navarro, Saúl Abenhamar; Carrillo, Esmeralda; Griñán-Lisón, Carmen; Martín, Ana; Perán, Macarena; Marchal, Juan Antonio; Boulaiz, Houria

2016-09-01

Cancer is considered the second leading cause of death worldwide despite the progress made in early detection and advances in classical therapies. Advancing in the fight against cancer requires the development of novel strategies, and the suicide gene transfer to tumor cells is providing new possibilities for cancer therapy. In this manuscript, authors present an overview of suicide gene systems and the latest innovations done to enhance cancer suicide gene therapy strategies by i) improving vectors for targeted gene delivery using tissue specific promoter and receptors; ii) modification of the tropism; and iii) combining suicide genes and/or classical therapies for cancer. Finally, the authors highlight the main challenges to be addressed in the future. Even if many efforts are needed for suicide gene therapy to be a real alternative for cancer treatment, we believe that the significant progress made in the knowledge of cancer biology and characterization of cancer stem cells accompanied by the development of novel targeted vectors will enhance the effectiveness of this type of therapeutic strategy. Moreover, combined with current treatments, suicide gene therapy will improve the clinical outcome of patients with cancer in the future.

Insulin-like growth factor-I gene therapy reverses morphologic changes and reduces hyperprolactinemia in experimental rat prolactinomas

Directory of Open Access Journals (Sweden)

Bracamonte Maria I

2008-01-01

Full Text Available Abstract Background The implementation of gene therapy for the treatment of pituitary tumors emerges as a promising complement to surgery and may have distinct advantages over radiotherapy for this type of tumors. Up to now, suicide gene therapy has been the main experimental approach explored to treat experimental pituitary tumors. In the present study we assessed the effectiveness of insulin-like growth factor I (IGF-I gene therapy for the treatment of estrogen-induced prolactinomas in rats. Results Female Sprague Dawley rats were subcutaneously implanted with silastic capsules filled with 17-β estradiol (E2 in order to induce pituitary prolactinomas. Blood samples were taken at regular intervals in order to measure serum prolactin (PRL. As expected, serum PRL increased progressively and 23 days after implanting the E2 capsules (Experimental day 0, circulating PRL had undergone a 3–4 fold increase. On Experimental day 0 part of the E2-implanted animals received a bilateral intrapituitary injection of either an adenoviral vector expressing the gene for rat IGF-I (RAd-IGFI, or a vector (RAd-GFP expressing the gene for green fluorescent protein (GFP. Seven days post vector injection all animals were sacrificed and their pituitaries morphometrically analyzed to evaluate changes in the lactotroph population. RAd-IGFI but not RAd-GFP, induced a significant fall in serum PRL. Furthermore, RAd-IGFI but not RAd-GFP significantly reversed the increase in lactotroph size (CS and volume density (VD induced by E2 treatment. Conclusion We conclude that IGF-I gene therapy constitutes a potentially useful intervention for the treatment of prolactinomas and that bioactive peptide gene delivery may open novel therapeutic avenues for the treatment of pituitary tumors.

Gene Therapy for Color Blindness.

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Hassall, Mark M; Barnard, Alun R; MacLaren, Robert E

2017-12-01

Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in CNGA3 , CNGB3 , GNAT2 , PDE6H , PDE6C , or ATF6 . Animal models of Cnga3 , Cngb3 , and Gnat2 have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a Cnga3 -/- mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.

Imaging reporter gene for monitoring gene therapy

International Nuclear Information System (INIS)

Beco, V. de; Baillet, G.; Tamgac, F.; Tofighi, M.; Weinmann, P.; Vergote, J.; Moretti, J.L.; Tamgac, G.

2002-01-01

Scintigraphic images can be obtained to document gene function at cellular level. This approach is presented here and the use of a reporter gene to monitor gene therapy is described. Two main ways are presented: either the use of a reporter gene coding for an enzyme the action of which will be monitored by radiolabeled pro-drug, or a cellular receptor gene, the action of which is documented by a radio labeled cognate receptor ligand. (author)

Multi-parametric monitoring and assessment of high-intensity focused ultrasound (HIFU) boiling by harmonic motion imaging for focused ultrasound (HMIFU): an ex vivo feasibility study

International Nuclear Information System (INIS)

Hou, Gary Y; Marquet, Fabrice; Wang, Shutao; Konofagou, Elisa E

2014-01-01

Harmonic motion imaging for focused ultrasound (HMIFU) is a recently developed high-intensity focused ultrasound (HIFU) treatment monitoring method with feasibilities demonstrated in vitro and in vivo. Here, a multi-parametric study is performed to investigate both elastic and acoustics-independent viscoelastic tissue changes using the Harmonic Motion Imaging (HMI) displacement, axial compressive strain and change in relative phase shift during high energy HIFU treatment with tissue boiling. Forty three (n = 43) thermal lesions were formed in ex vivo canine liver specimens (n = 28). Two-dimensional (2D) transverse HMI displacement maps were also obtained before and after lesion formation. The same method was repeated in 10 s, 20 s and 30 s HIFU durations at three different acoustic powers of 8, 10, and 11 W, which were selected and verified as treatment parameters capable of inducing boiling using both thermocouple and passive cavitation detection (PCD) measurements. Although a steady decrease in the displacement, compressive strain, and relative change in the focal phase shift (Δϕ) were obtained in numerous cases, indicating an overall increase in relative stiffness, the study outcomes also showed that during boiling, a reverse lesion-to-background displacement contrast was detected, indicating potential change in tissue absorption, geometrical change and/or, mechanical gelatification or pulverization. Following treatment, corresponding 2D HMI displacement images of the thermal lesions also mapped consistent discrepancy in the lesion-to-background displacement contrast. Despite the expectedly chaotic changes in acoustic properties with boiling, the relative change in phase shift showed a consistent decrease, indicating its robustness to monitor biomechanical properties independent of the acoustic property changes throughout the HIFU treatment. In addition, the 2D HMI displacement images confirmed and indicated the increase in the thermal lesion size with

Stem Cell Gene Therapy for Fanconi Anemia: Report from the 1st International Fanconi Anemia Gene Therapy Working Group Meeting

Science.gov (United States)

Tolar, Jakub; Adair, Jennifer E; Antoniou, Michael; Bartholomae, Cynthia C; Becker, Pamela S; Blazar, Bruce R; Bueren, Juan; Carroll, Thomas; Cavazzana-Calvo, Marina; Clapp, D Wade; Dalgleish, Robert; Galy, Anne; Gaspar, H Bobby; Hanenberg, Helmut; Von Kalle, Christof; Kiem, Hans-Peter; Lindeman, Dirk; Naldini, Luigi; Navarro, Susana; Renella, Raffaele; Rio, Paula; Sevilla, Julián; Schmidt, Manfred; Verhoeyen, Els; Wagner, John E; Williams, David A; Thrasher, Adrian J

2011-01-01

Survival rates after allogeneic hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) have increased dramatically since 2000. However, the use of autologous stem cell gene therapy, whereby the patient's own blood stem cells are modified to express the wild-type gene product, could potentially avoid the early and late complications of allogeneic HCT. Over the last decades, gene therapy has experienced a high degree of optimism interrupted by periods of diminished expectation. Optimism stems from recent examples of successful gene correction in several congenital immunodeficiencies, whereas diminished expectations come from the realization that gene therapy will not be free of side effects. The goal of the 1st International Fanconi Anemia Gene Therapy Working Group Meeting was to determine the optimal strategy for moving stem cell gene therapy into clinical trials for individuals with FA. To this end, key investigators examined vector design, transduction method, criteria for large-scale clinical-grade vector manufacture, hematopoietic cell preparation, and eligibility criteria for FA patients most likely to benefit. The report summarizes the roadmap for the development of gene therapy for FA. PMID:21540837

Shock wave induced sonoporation and gene transfer

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Miller, Douglas L.

2003-10-01

During shockwave (SW) treatment, cavitation activity can be applied for cell killing. A bonus is that some surviving cells appear to be briefly permeabilized, or sonoporated, allowing them to take up large molecules including DNA. In vitro research has indicated that as the number of SW increased, survival declined exponentially but the number of sonoporated cells increased to better than 50% of survivors for 1000 SW. In vivo tests have demonstrated SW-induced tumor ablation could indeed be accompanied by the transfection of marker plasmids into mouse B16 melanoma tumors in vivo. With intratumor injection of plasmid DNA and air bubbles, significant results were obtained for only 400 SW. In a trial of cancer therapy, the effects of 500 SW combined with interleukin-12 immuno-gene therapy was observed on the progression of two mouse tumors, B16 melanoma and RENCA renal carcinoma. The combination of SW and IL-12 plasmid injection provided a statistically significant inhibition of tumor growth relative to SW alone for both tumor models, demonstrating feasibility for this treatment method. In the future, the development of intravenous gene delivery and improved transfection, together with image-guided ultrasound treatment, should lead to the clinical application of ultrasound enhanced gene therapy. [Work supported by NIH Grant No. EB002782.

Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy.

Directory of Open Access Journals (Sweden)

Brandon K Sack

Full Text Available The major complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors against factor VIII (FVIII. The current method for eradicating inhibitors, termed immune tolerance induction (ITI, is costly and protracted. Clinical protocols that prevent rather than treat inhibitors are not yet established. Liver-directed gene therapy hopes to achieve long-term correction of the disease while also inducing immune tolerance. We sought to investigate the use of adeno-associated viral (serotype 8 gene transfer to induce tolerance to human B domain deleted FVIII in hemophilia A mice. We administered an AAV8 vector with either human B domain deleted FVIII or a codon-optimized transgene, both under a liver-specific promoter to two strains of hemophilia A mice. Protein therapy or gene therapy was given either alone or in conjunction with anti-CD20 antibody-mediated B cell depletion. Gene therapy with a low-expressing vector resulted in sustained near-therapeutic expression. However, supplementary protein therapy revealed that gene transfer had sensitized mice to hFVIII in a high-responder strain but not in mice of a low-responding strain. This heightened response was ameliorated when gene therapy was delivered with anti-murine CD20 treatment. Transient B cell depletion prevented inhibitor formation in protein therapy, but failed to achieve a sustained hypo-responsiveness. Importantly, use of a codon-optimized hFVIII transgene resulted in sustained therapeutic expression and tolerance without a need for B cell depletion. Therefore, anti-CD20 may be beneficial in preventing vector-induced immune priming to FVIII, but higher levels of liver-restricted expression are preferred for tolerance.

Imaging after vascular gene therapy

International Nuclear Information System (INIS)

Manninen, Hannu I.; Yang, Xiaoming

2005-01-01

Targets for cardiovascular gene therapy currently include limiting restenosis after balloon angioplasty and stent placement, inhibiting vein bypass graft intimal hyperplasia/stenosis, therapeutic angiogenesis for cardiac and lower-limb ischemia, and prevention of thrombus formation. While catheter angiography is still standard method to follow-up vascular gene transfer, other modern imaging techniques, especially intravascular ultrasound (IVUS), magnetic resonance (MR), and positron emission tomography (PET) imaging provide complementary information about the therapeutic effect of vascular gene transfer in humans. Although molecular imaging of therapeutic gene expression in the vasculatures is still in its technical development phase, it has already offered basic medical science an extremely useful in vivo evaluation tool for non- or minimally invasive imaging of vascular gene therapy

Oncological and functional outcomes of elderly men treated with HIFU vs. minimally invasive radical prostatectomy: A propensity score analysis.

Science.gov (United States)

Capogrosso, Paolo; Barret, Eric; Sanchez-Salas, Rafael; Nunes-Silva, Igor; Rozet, François; Galiano, Marc; Ventimiglia, Eugenio; Briganti, Alberto; Salonia, Andrea; Montorsi, Francesco; Cathelineau, Xavier

2018-01-01

To assess outcomes of whole gland high-intensity focused ultrasound (HIFU) as compared with minimally-invasive radical prostatectomy (MIRP) in elderly patients. Patients aged ≥70 years with, cT1-cT2 disease, biopsy Gleason score (GS) 3 + 3 or 3 + 4 and preoperative PSA ≤10 ng/mL were submitted to either whole-gland HIFU or MIRP. Propensity-score matching analysis was performed to ensure the baseline equivalence of groups. Follow-up visits were routinely performed assessing PSA and urinary function according to the International Continence Score (ICS) and the International Prostatic Symptoms Score (IPSS) questionnaires. Estimated rates of salvage-treatment free survival (SFS) overall-survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MTS) were assessed and compared. Overall, 84 (33.3%) and 168 (66.7%) patients were treated with HIFU and MIRP, respectively. MIRP was associated with a 5-yrs SFS of 93.4% compared to 74.8% for HIFU (p < 0.01). The two groups did not differ in terms of OS and MTS. No cancer-related deaths were registered. Patients treated with HIFU showed better short-term (6-mos) continence outcomes [mean-ICS: 1.7 vs. 4.8; p = 0.005] but higher IPSS mean scores at 12-mos assessment. A comparable rate of patients experiencing post-treatment Clavien-Dindo grade ≥III complications was observed within the two groups. Whole-gland HIFU is a feasible treatment in elderly men with low-to intermediate-risk PCa and could be considered for patients either unfit for surgery, or willing a non-invasive treatment with a low morbidity burden, although a non-negligible risk of requiring subsequent treatment for recurrence should be expected. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

Science.gov (United States)

Lytle, Allison M; Brown, Harrison C; Paik, Na Yoon; Knight, Kristopher A; Wright, J Fraser; Spencer, H Trent; Doering, Christopher B

2016-01-01

Immune responses to coagulation factors VIII (FVIII) and IX (FIX) represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC) retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV)-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV) vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV. PMID:26909355

Prediction of thermal coagulation from the instantaneous strain distribution induced by high-intensity focused ultrasound

Science.gov (United States)

Iwasaki, Ryosuke; Takagi, Ryo; Tomiyasu, Kentaro; Yoshizawa, Shin; Umemura, Shin-ichiro

2017-07-01

The targeting of the ultrasound beam and the prediction of thermal lesion formation in advance are the requirements for monitoring high-intensity focused ultrasound (HIFU) treatment with safety and reproducibility. To visualize the HIFU focal zone, we utilized an acoustic radiation force impulse (ARFI) imaging-based method. After inducing displacements inside tissues with pulsed HIFU called the push pulse exposure, the distribution of axial displacements started expanding and moving. To acquire RF data immediately after and during the HIFU push pulse exposure to improve prediction accuracy, we attempted methods using extrapolation estimation and applying HIFU noise elimination. The distributions going back in the time domain from the end of push pulse exposure are in good agreement with tissue coagulation at the center. The results suggest that the proposed focal zone visualization employing pulsed HIFU entailing the high-speed ARFI imaging method is useful for the prediction of thermal coagulation in advance.

Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy

International Nuclear Information System (INIS)

Gopinath, P; Ghosh, Siddhartha Sankar; Gogoi, Sonit Kumar; Chattopadhyay, Arun

2008-01-01

The impact of manufactured nanomaterials on human health and the environment is a major concern for commercial use of nanotechnology based products. A judicious choice of selective usage, lower nanomaterial concentration and use in combination with conventional therapeutic materials may provide the best solution. For example, silver nanoparticles (Ag NPs) are known to be bactericidal and also cytotoxic to mammalian cells. Herein, we investigate the molecular mechanism of Ag NP mediated cytotoxicity in both cancer and non-cancer cells and find that optimum particle concentration leads to programmed cell death in vitro. Also, the benefit of the cytotoxic effects of Ag NPs was tested for therapeutic use in conjunction with conventional gene therapy. The synergistic effect of Ag NPs on the uracil phosphoribosyltransferase expression system sensitized the cells more towards treatment with the drug 5-fluorouracil. Induction of the apoptotic pathway makes Ag NPs a representative of a new chemosensitization strategy for future application in gene therapy

Adenovirus-mediated IL-12 gene therapy in combination with radiotherapy for murine liver cancer

International Nuclear Information System (INIS)

Wei Daoyan; Dai Bingbing; Wang Zhonghe; Chen Shishu

2001-01-01

Objective: To investigate the synergistic antitumor effects of adenovirus-mediated IL-12 gene therapy in combination with radiotherapy in mice bearing liver cancer. Methods: Balb/c mice bearing liver cancer received the treatment at day 1 with tumor local irradiation (TLI) of 20 Gy or mask irradiation when tumor size reached 0.6-1.0 cm. Within 1 hour after irradiation, adenovirus containing IL-12 gene or PBS was intra-tumor injected once a week. Forty-eight hours after the second injection, IFN-γ levels in sera and the supernatant of cultured spleen cells were assayed by ELISA, CTL activity of spleen cells was measured by 3 H-TdR release assay, and phenotypes of tumor-infiltrating lymphocytes were analysed by immunohistochemical staining. Results: The growth of tumors in animals treated with a combination of IL-12 gene therapy and TLI was inhibited more significantly than those with either single treatment (P + and CD8 + lymphocyte infiltration and tumor-specific cytolytic activities, and the levels of IFN-γ in sera were higher in IL-12 gene therapy and IL-12 gene therapy combined with TLI groups. Conclusion: These results suggest that IL-12 gene therapy combined with radiotherapy is more effective than both single treatment modalities and can induce specific antitumor immuno-response greatly

Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice.

Science.gov (United States)

Baumgartner, C K; Mattson, J G; Weiler, H; Shi, Q; Montgomery, R R

2017-01-01

Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of

Keratinocyte Growth Factor Gene Electroporation into Skeletal Muscle as a Novel Gene Therapeutic Approach for Elastase-Induced Pulmonary Emphysema in Mice

International Nuclear Information System (INIS)

Tobinaga, Shuichi; Matsumoto, Keitaro; Nagayasu, Takeshi; Furukawa, Katsuro; Abo, Takafumi; Yamasaki, Naoya; Tsuchiya, Tomoshi; Miyazaki, Takuro; Koji, Takehiko

2015-01-01

Pulmonary emphysema is a progressive disease with airspace destruction and an effective therapy is needed. Keratinocyte growth factor (KGF) promotes pulmonary epithelial proliferation and has the potential to induce lung regeneration. The aim of this study was to determine the possibility of using KGF gene therapy for treatment of a mouse emphysema model induced by porcine pancreatic elastase (PPE). Eight-week-old BALB/c male mice treated with intra-tracheal PPE administration were transfected with 80 μg of a recombinant human KGF (rhKGF)-expressing FLAG-CMV14 plasmid (pKGF-FLAG gene), or with the pFLAG gene expressing plasmid as a control, into the quadriceps muscle by electroporation. In the lung, the expression of proliferating cell nuclear antigen (PCNA) was augmented, and surfactant protein A (SP-A) and KGF receptor (KGFR) were co-expressed in PCNA-positive cells. Moreover, endogenous KGF and KGFR gene expression increased significantly by pKGF-FLAG gene transfection. Arterial blood gas analysis revealed that the PaO 2 level was not significantly reduced on day 14 after PPE instillation with pKGF-FLAG gene transfection compared to that of normal mice. These results indicated that KGF gene therapy with electroporation stimulated lung epithelial proliferation and protected depression of pulmonary function in a mouse emphysema model, suggesting a possible method of treating pulmonary emphysema

Neonatal Gene Therapy for Hemophilia B by a Novel Adenovirus Vector Showing Reduced Leaky Expression of Viral Genes.

Science.gov (United States)

Iizuka, Shunsuke; Sakurai, Fuminori; Tachibana, Masashi; Ohashi, Kazuo; Mizuguchi, Hiroyuki

2017-09-15

Gene therapy during neonatal and infant stages is a promising approach for hemophilia B, a congenital disorder caused by deficiency of blood coagulation factor IX (FIX). An adenovirus (Ad) vector has high potential for use in neonatal or infant gene therapy for hemophilia B due to its superior transduction properties; however, leaky expression of Ad genes often reduces the transduction efficiencies by Ad protein-mediated tissue damage. Here, we used a novel Ad vector, Ad-E4-122aT, which exhibits a reduction in the leaky expression of Ad genes in liver, in gene therapy studies for neonatal hemophilia B mice. Ad-E4-122aT exhibited significantly higher transduction efficiencies than a conventional Ad vector in neonatal mice. In neonatal hemophilia B mice, a single neonatal injection of Ad-E4-122aT expressing human FIX (hFIX) (Ad-E4-122aT-AHAFIX) maintained more than 6% of the normal plasma hFIX activity levels for approximately 100 days. Sequential administration of Ad-E4-122aT-AHAFIX resulted in more than 100% of the plasma hFIX activity levels for more than 100 days and rescued the bleeding phenotypes of hemophilia B mice. In addition, immunotolerance to hFIX was induced by Ad-E4-122aT-AHAFIX administration in neonatal hemophilia B mice. These results indicated that Ad-E4-122aT is a promising gene delivery vector for neonatal or infant gene therapy for hemophilia B.

Reprogrammed chondrocytes engineered to produce IL-12 provide novel ex vivo immune-gene therapy for cancer.

Science.gov (United States)

Tada, Hiroyuki; Kishida, Tsunao; Fujiwara, Hitoshi; Kosuga, Toshiyuki; Konishi, Hirotaka; Komatsu, Shuhei; Shiozaki, Atsushi; Ichikawa, Daisuke; Okamoto, Kazuma; Otsuji, Eigo; Mazda, Osam

2017-03-01

The somatic cell reprogramming technology was applied to a novel and promising ex vivo immune-gene therapy strategy for cancer. To establish a novel ex vivo cytokine gene therapy of cancer using the somatic cell reprogramming procedures. Mouse fibroblasts were converted into chondrocytes and subsequently transduced with IL-12 gene. The resultant IL-12 induced chondrogenic cells were irradiated with x-ray and inoculated into mice bearing CT26 colon cancer. The irradiation at 20 Gy or higher totally eliminated the proliferative potential of the cells, while less significantly influencing the IL-12 production from the cells. An inoculation of the irradiated IL-12 induced chondrogenic cells significantly suppressed tumor by inducing tumor-specific cytotoxic T lymphocytes, enhancing natural killer tumoricidal activity and inhibiting tumor neoangiogenesis in the mice. The somatic cell reprogramming procedures may provide a novel and effective means to treat malignancies.

Radiopharmaceuticals to monitor the expression of transferred genes in gene transfer therapy

International Nuclear Information System (INIS)

Wiebe, L. I.

1997-01-01

The development and application of radiopharmaceuticals has, in many instances, been based on the pharmacological properties of therapeutic agents. The molecular biology-biotechnology revolution has had an important impact on treatment of diseases, in part through the reduced toxicity of 'biologicals', in part because of their specificity for interaction at unique molecular sites and in part because of their selective delivery to the target site. Immunotherapeutic approaches include the use of monoclonal antibodies (MABs), MAB-fragments and chemotactic peptides. Such agents currently form the basis of both diagnostic and immunotherapeutic radiopharmaceuticals. More recently, gene transfer techniques have been advanced to the point that a new molecular approach, gene therapy, has become a reality. Gene therapy offers an opportunity to attack disease at its most fundamental level. The therapeutic mechanism is based on the expression of a specific gene or genes, the product of which will invoke immunological, receptor-based or enzyme-based therapeutic modalities. Several approaches to gene therapy of cancer have been envisioned, the most clinically-advanced concepts involving the introduction of genes that will encode for molecular targets nor normally found in healthy mammalian cells. A number of gene therapy clinical trials are based on the introduction of the Herpes simplex virus type-1 (HSV-1) gene that encodes for viral thymidine kinase (tk+). Once HSV-1 tk+ is expressed in the target (cancer) cell, therapy can be effected by the administration of a highly molecularly-targeted and systemically non-toxic antiviral drug such as ganciclovir. The development of radiodiagnostic imaging in gene therapy will be reviewed, using HSV-1 tk+ and radioiodinated IVFRU as a basis for development of the theme. Molecular targets that could be exploited in gene therapy, other than tk+, will be identified

Radiopharmaceuticals to monitor the expression of transferred genes in gene transfer therapy

Energy Technology Data Exchange (ETDEWEB)

Wiebe, L I [University of Alberta, Edmonton (Canada). Noujaim Institute for Pharmaceutical Oncology Research

1997-10-01

The development and application of radiopharmaceuticals has, in many instances, been based on the pharmacological properties of therapeutic agents. The molecular biology-biotechnology revolution has had an important impact on treatment of diseases, in part through the reduced toxicity of `biologicals`, in part because of their specificity for interaction at unique molecular sites and in part because of their selective delivery to the target site. Immunotherapeutic approaches include the use of monoclonal antibodies (MABs), MAB-fragments and chemotactic peptides. Such agents currently form the basis of both diagnostic and immunotherapeutic radiopharmaceuticals. More recently, gene transfer techniques have been advanced to the point that a new molecular approach, gene therapy, has become a reality. Gene therapy offers an opportunity to attack disease at its most fundamental level. The therapeutic mechanism is based on the expression of a specific gene or genes, the product of which will invoke immunological, receptor-based or enzyme-based therapeutic modalities. Several approaches to gene therapy of cancer have been envisioned, the most clinically-advanced concepts involving the introduction of genes that will encode for molecular targets nor normally found in healthy mammalian cells. A number of gene therapy clinical trials are based on the introduction of the Herpes simplex virus type-1 (HSV-1) gene that encodes for viral thymidine kinase (tk+). Once HSV-1 tk+ is expressed in the target (cancer) cell, therapy can be effected by the administration of a highly molecularly-targeted and systemically non-toxic antiviral drug such as ganciclovir. The development of radiodiagnostic imaging in gene therapy will be reviewed, using HSV-1 tk+ and radioiodinated IVFRU as a basis for development of the theme. Molecular targets that could be exploited in gene therapy, other than tk+, will be identified

HIV-derived vectors for gene therapy targeting dendritic cells.

Science.gov (United States)

Rossetti, Maura; Cavarelli, Mariangela; Gregori, Silvia; Scarlatti, Gabriella

2013-01-01

Human immunodeficiency virus type 1 (HIV-1)-derived lentiviral vectors (LV) have the potential to mediate stable therapeutic gene transfer. However, similarly to other viral vectors, their benefit is compromised by the induction of an immune response toward transgene-expressing cells that closely mimics antiviral immunity. LV share with the parental HIV the ability to activate dendritic cells (DC), while lack the peculiar ability of subverting DC functions, which is responsible for HIV immune escape. Understanding the interaction between LV and DC, with plasmacytoid and myeloid DC playing fundamental and distinct roles, has paved the way to novel approaches aimed at regulating transgene-specific immune responses. Thanks to the ability to target either DC subsets LV might be a powerful tool to induce immunity (i.e., gene therapy of cancer), cell death (i.e., in HIV/AIDS infection), or tolerance (i.e., gene therapy strategies for monogenic diseases). In this chapter, similarities and differences between the LV-mediated and HIV-mediated induction of immune responses, with specific focus on their interactions with DC, are discussed.

Bone Marrow Gene Therapy for HIV/AIDS

Directory of Open Access Journals (Sweden)

Elena Herrera-Carrillo

2015-07-01

Full Text Available Bone marrow gene therapy remains an attractive option for treating chronic immunological diseases, including acquired immunodeficiency syndrome (AIDS caused by human immunodeficiency virus (HIV. This technology combines the differentiation and expansion capacity of hematopoietic stem cells (HSCs with long-term expression of therapeutic transgenes using integrating vectors. In this review we summarize the potential of bone marrow gene therapy for the treatment of HIV/AIDS. A broad range of antiviral strategies are discussed, with a particular focus on RNA-based therapies. The idea is to develop a durable gene therapy that lasts the life span of the infected individual, thus contrasting with daily drug regimens to suppress the virus. Different approaches have been proposed to target either the virus or cellular genes encoding co-factors that support virus replication. Some of these therapies have been tested in clinical trials, providing proof of principle that gene therapy is a safe option for treating HIV/AIDS. In this review several topics are discussed, ranging from the selection of the antiviral molecule and the viral target to the optimal vector system for gene delivery and the setup of appropriate preclinical test systems. The molecular mechanisms used to formulate a cure for HIV infection are described, including the latest antiviral strategies and their therapeutic applications. Finally, a potent combination of anti-HIV genes based on our own research program is described.

Role of PET in gene therapy

International Nuclear Information System (INIS)

Lee, Kyung Han

2002-01-01

In addition to the well-established use of positron emission tomography (PET) in clinical oncology, novel roles for PET are rapidly emerging in the field of gene therapy. Methods for controlled gene delivery to living bodies, made available through advances in molecular biology, are currently being employed in animals for reasearch purposes and in humans to treat diseases such as cancer. Although gene therapy is still in its early developmental stage, it is perceived that many serious illnesses could be treated successfully by the use of therapeutic gene delivery. A major challenge for the widespread use of human gene therapy is to achieve a controlled and effective delivery of foreign genes to target cells and subsequently, adequate levels of expression. As such, the availability of noninvasive imaging methods to accurately assess the location, duration, and level of transgene expression is critical for optimizing gene therapy strategies. Current endeavors to achieve this goal include methods that utilize magnetic resonance imaging, optical imaging, and nuclear imaging techniques. As for PET, reporter systems that utilize gene encoding enzymes that accumulate postion labeled substrates and those transcribing surface receptors that bind specific positron labeled ligands have been successfully developed. More recent advances in this area include improved reporter gene constructs and radiotracers, introduction of potential strategies to monitor endogenous gene expression, and human pilot studies evaluating the distribution and safety of reporter PET tracers. The remarkably rapid progress occuring in gene imaging technology indicates its importance and wide range of application. As such, gene imaging is likely to become a major and exciting new area for future application of PET technology

Role of PET in gene therapy

Energy Technology Data Exchange (ETDEWEB)

Lee, Kyung Han [School of Medicine, Sungkyunkwan Univ., Seoul (Korea, Republic of)

2002-02-01

In addition to the well-established use of positron emission tomography (PET) in clinical oncology, novel roles for PET are rapidly emerging in the field of gene therapy. Methods for controlled gene delivery to living bodies, made available through advances in molecular biology, are currently being employed in animals for reasearch purposes and in humans to treat diseases such as cancer. Although gene therapy is still in its early developmental stage, it is perceived that many serious illnesses could be treated successfully by the use of therapeutic gene delivery. A major challenge for the widespread use of human gene therapy is to achieve a controlled and effective delivery of foreign genes to target cells and subsequently, adequate levels of expression. As such, the availability of noninvasive imaging methods to accurately assess the location, duration, and level of transgene expression is critical for optimizing gene therapy strategies. Current endeavors to achieve this goal include methods that utilize magnetic resonance imaging, optical imaging, and nuclear imaging techniques. As for PET, reporter systems that utilize gene encoding enzymes that accumulate postion labeled substrates and those transcribing surface receptors that bind specific positron labeled ligands have been successfully developed. More recent advances in this area include improved reporter gene constructs and radiotracers, introduction of potential strategies to monitor endogenous gene expression, and human pilot studies evaluating the distribution and safety of reporter PET tracers. The remarkably rapid progress occuring in gene imaging technology indicates its importance and wide range of application. As such, gene imaging is likely to become a major and exciting new area for future application of PET technology.

Photoacoustic detection and optical spectroscopy of high-intensity focused ultrasound-induced thermal lesions in biologic tissue

Energy Technology Data Exchange (ETDEWEB)

Alhamami, Mosa; Kolios, Michael C.; Tavakkoli, Jahan, E-mail: jtavakkoli@ryerson.ca [Department of Physics, Ryerson University, 350 Victoria Street, Toronto, Ontario M5B 2K3 (Canada)

2014-05-15

Purpose: The aims of this study are: (a) to investigate the capability of photoacoustic (PA) method in detecting high-intensity focused ultrasound (HIFU) treatments in muscle tissuesin vitro; and (b) to determine the optical properties of HIFU-treated and native tissues in order to assist in the interpretation of the observed contrast in PA detection of HIFU treatments. Methods: A single-element, spherically concaved HIFU transducer with a centre frequency of 1 MHz was utilized to create thermal lesions in chicken breast tissuesin vitro. To investigate the detectability of HIFU treatments photoacoustically, PA detection was performed at 720 and 845 nm on seven HIFU-treated tissue samples. Within each tissue sample, PA signals were acquired from 22 locations equally divided between two regions of interest within two volumes in tissue – a HIFU-treated volume and an untreated volume. Optical spectroscopy was then carried out on 10 HIFU-treated chicken breast specimens in the wavelength range of 500–900 nm, in 1-nm increments, using a spectrophotometer with an integrating sphere attachment. The authors’ optical spectroscopy raw data (total transmittance and diffuse reflectance) were used to obtain the optical absorption and reduced scattering coefficients of HIFU-induced thermal lesions and native tissues by employing the inverse adding-doubling method. The aforementioned interaction coefficients were subsequently used to calculate the effective attenuation coefficient and light penetration depth of HIFU-treated and native tissues in the wavelength range of 500–900 nm. Results: HIFU-treated tissues produced greater PA signals than native tissues at 720 and 845 nm. At 720 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.68 ± 0.25 (mean ± standard error of the mean). At 845 nm, the averaged ratio of the peak-to-peak PA signal amplitude of HIFU-treated tissue to that of native tissue was 3.75 �

Suicide genes or p53 gene and p53 target genes as targets for cancer gene therapy by ionizing radiation

International Nuclear Information System (INIS)

Liu Bing; Chinese Academy of Sciences, Beijing; Zhang Hong

2005-01-01

Radiotherapy has some disadvantages due to the severe side-effect on the normal tissues at a curative dose of ionizing radiation (IR). Similarly, as a new developing approach, gene therapy also has some disadvantages, such as lack of specificity for tumors, limited expression of therapeutic gene, potential biological risk. To certain extent, above problems would be solved by the suicide genes or p53 gene and its target genes therapies targeted by ionizing radiation. This strategy not only makes up the disadvantage from radiotherapy or gene therapy alone, but also promotes success rate on the base of lower dose. By present, there have been several vectors measuring up to be reaching clinical trials. This review focused on the development of the cancer gene therapy through suicide genes or p53 and its target genes mediated by IR. (authors)

Characterization of HIFU transducers designed for sonochemistry application: Cavitation distribution and quantification

Czech Academy of Sciences Publication Activity Database

Hallez, L.; Touyeraz, F.; Hihn, J. Y.; Klíma, Jiří; Guey, J.-L.; Spajer, M.; Bailly, Y.

2010-01-01

Roč. 50, č. 2 (2010), s. 310-317 ISSN 0041-624X Institutional research plan: CEZ:AV0Z40400503 Keywords : HIFU * acoustic cavitation * MBSCL threshold * sonoreactors Subject RIV: CG - Electrochemistry Impact factor: 1.599, year: 2010

Advances in study of reporter gene imaging for monitoring gene therapy

International Nuclear Information System (INIS)

Mu Chuanjie; Zhou Jiwen

2003-01-01

To evaluate the efficiency of gene therapy, it is requisite to monitor localization and expression of the therapeutic gene in vivo. Monitoring expression of reporter gene using radionuclide reporter gene technique is the best method. Adenoviral vectors expressing reporter gene are constructed using gene fusion, bicistronic, double promoter or bidirectional transcriptional recombination techniques, and transferred into target cells and tissues, then injected radiolabeled reporter probes which couple to the reporter genes. The reporter genes can be imaged invasively, repeatedly, quantitatively with γ-camera, PET and SPECT. Recently, several reporter gene and reporter probe systems have been used in studies of gene therapy. The part of them has been used for clinic trials

Bacterial Toxins for Oncoleaking Suicidal Cancer Gene Therapy.

Science.gov (United States)

Pahle, Jessica; Walther, Wolfgang

For suicide gene therapy, initially prodrug-converting enzymes (gene-directed enzyme-producing therapy, GDEPT) were employed to intracellularly metabolize non-toxic prodrugs into toxic compounds, leading to the effective suicidal killing of the transfected tumor cells. In this regard, the suicide gene therapy has demonstrated its potential for efficient tumor eradication. Numerous suicide genes of viral or bacterial origin were isolated, characterized, and extensively tested in vitro and in vivo, demonstrating their therapeutic potential even in clinical trials to treat cancers of different entities. Apart from this, growing efforts are made to generate more targeted and more effective suicide gene systems for cancer gene therapy. In this regard, bacterial toxins are an alternative to the classical GDEPT strategy, which add to the broad spectrum of different suicide approaches. In this context, lytic bacterial toxins, such as streptolysin O (SLO) or the claudin-targeted Clostridium perfringens enterotoxin (CPE) represent attractive new types of suicide oncoleaking genes. They permit as pore-forming proteins rapid and also selective toxicity toward a broad range of cancers. In this chapter, we describe the generation and use of SLO as well as of CPE-based gene therapies for the effective tumor cell eradication as promising, novel suicide gene approach particularly for treatment of therapy refractory tumors.

Effects of FVIII immunity on hepatocyte and hematopoietic stem cell–directed gene therapy of murine hemophilia A

Directory of Open Access Journals (Sweden)

Allison M Lytle

2016-01-01

Full Text Available Immune responses to coagulation factors VIII (FVIII and IX (FIX represent primary obstacles to hemophilia treatment. Previously, we showed that hematopoietic stem cell (HSC retroviral gene therapy induces immune nonresponsiveness to FVIII in both naive and preimmunized murine hemophilia A settings. Liver-directed adeno-associated viral (AAV-FIX vector gene transfer achieved similar results in preclinical hemophilia B models. However, as clinical immune responses to FVIII and FIX differ, we investigated the ability of liver-directed AAV-FVIII gene therapy to affect FVIII immunity in hemophilia A mice. Both FVIII naive and preimmunized mice were administered recombinant AAV8 encoding a liver-directed bioengineered FVIII expression cassette. Naive animals receiving high or mid-doses subsequently achieved near normal FVIII activity levels. However, challenge with adjuvant-free recombinant FVIII induced loss of FVIII activity and anti-FVIII antibodies in mid-dose, but not high-dose AAV or HSC lentiviral (LV vector gene therapy cohorts. Furthermore, unlike what was shown previously for FIX gene transfer, AAV-FVIII administration to hemophilia A inhibitor mice conferred no effect on anti-FVIII antibody or inhibitory titers. These data suggest that functional differences exist in the immune modulation achieved to FVIII or FIX in hemophilia mice by gene therapy approaches incorporating liver-directed AAV vectors or HSC-directed LV.

Radiation-induced gene expression in human subcutaneous fibroblasts is predictive of radiation-induced fibrosis

DEFF Research Database (Denmark)

Rødningen, Olaug Kristin; Børresen-Dale, Anne-Lise; Alsner, Jan

2008-01-01

BACKGROUND AND PURPOSE: Breast cancer patients show a large variation in normal tissue reactions after ionizing radiation (IR) therapy. One of the most common long-term adverse effects of ionizing radiotherapy is radiation-induced fibrosis (RIF), and several attempts have been made over the last...... years to develop predictive assays for RIF. Our aim was to identify basal and radiation-induced transcriptional profiles in fibroblasts from breast cancer patients that might be related to the individual risk of RIF in these patients. MATERIALS AND METHODS: Fibroblast cell lines from 31 individuals......-treated fibroblasts. Transcriptional differences in basal and radiation-induced gene expression profiles were investigated using 15K cDNA microarrays, and results analyzed by both SAM and PAM. RESULTS: Sixty differentially expressed genes were identified by applying SAM on 10 patients with the highest risk of RIF...

Progresses towards safe and efficient gene therapy vectors.

Science.gov (United States)

Chira, Sergiu; Jackson, Carlo S; Oprea, Iulian; Ozturk, Ferhat; Pepper, Michael S; Diaconu, Iulia; Braicu, Cornelia; Raduly, Lajos-Zsolt; Calin, George A; Berindan-Neagoe, Ioana

2015-10-13

The emergence of genetic engineering at the beginning of the 1970's opened the era of biomedical technologies, which aims to improve human health using genetic manipulation techniques in a clinical context. Gene therapy represents an innovating and appealing strategy for treatment of human diseases, which utilizes vehicles or vectors for delivering therapeutic genes into the patients' body. However, a few past unsuccessful events that negatively marked the beginning of gene therapy resulted in the need for further studies regarding the design and biology of gene therapy vectors, so that this innovating treatment approach can successfully move from bench to bedside. In this paper, we review the major gene delivery vectors and recent improvements made in their design meant to overcome the issues that commonly arise with the use of gene therapy vectors. At the end of the manuscript, we summarized the main advantages and disadvantages of common gene therapy vectors and we discuss possible future directions for potential therapeutic vectors.

Improved animal models for testing gene therapy for atherosclerosis.

Science.gov (United States)

Du, Liang; Zhang, Jingwan; De Meyer, Guido R Y; Flynn, Rowan; Dichek, David A

2014-04-01

Gene therapy delivered to the blood vessel wall could augment current therapies for atherosclerosis, including systemic drug therapy and stenting. However, identification of clinically useful vectors and effective therapeutic transgenes remains at the preclinical stage. Identification of effective vectors and transgenes would be accelerated by availability of animal models that allow practical and expeditious testing of vessel-wall-directed gene therapy. Such models would include humanlike lesions that develop rapidly in vessels that are amenable to efficient gene delivery. Moreover, because human atherosclerosis develops in normal vessels, gene therapy that prevents atherosclerosis is most logically tested in relatively normal arteries. Similarly, gene therapy that causes atherosclerosis regression requires gene delivery to an existing lesion. Here we report development of three new rabbit models for testing vessel-wall-directed gene therapy that either prevents or reverses atherosclerosis. Carotid artery intimal lesions in these new models develop within 2-7 months after initiation of a high-fat diet and are 20-80 times larger than lesions in a model we described previously. Individual models allow generation of lesions that are relatively rich in either macrophages or smooth muscle cells, permitting testing of gene therapy strategies targeted at either cell type. Two of the models include gene delivery to essentially normal arteries and will be useful for identifying strategies that prevent lesion development. The third model generates lesions rapidly in vector-naïve animals and can be used for testing gene therapy that promotes lesion regression. These models are optimized for testing helper-dependent adenovirus (HDAd)-mediated gene therapy; however, they could be easily adapted for testing of other vectors or of different types of molecular therapies, delivered directly to the blood vessel wall. Our data also supports the promise of HDAd to deliver long

Gene therapy for lung cancer.

Science.gov (United States)

Toloza, Eric M; Morse, Michael A; Lyerly, H Kim

2006-09-01

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer. (c) 2006 Wiley-Liss, Inc.

Immunological Monitoring to Rationally Guide AAV Gene Therapy

Directory of Open Access Journals (Sweden)

Cedrik Michael Britten

2013-09-01

Full Text Available Recent successes with adeno-associated virus (AAV-based gene therapies fuel the hope for new treatments for hereditary diseases. Pre-existing as well as therapy-induced immune responses against both AAV and the encoded transgenes have been described and may impact on safety and efficacy of gene-therapy approaches. Consequently, monitoring of vector- and transgene-specific immunity is mandated and may rationally guide clinical development. Next to the humoral immune response, the cellular response is central in our understanding of the host reaction in gene therapy. But in contrast to the monitoring of antibodies, which has matured over many decades, sensitive and robust monitoring of T cells is a relatively new development. To make cellular immune assessments fit for purpose, investigators need to know, control and report the critical assay variables that influence the results. In addition, the quality of immune assays needs to be continuously adjusted to allow for exploratory hypothesis generation in early stages and confirmatory hypothesis validation in later stages of clinical development. The concept of immune assay harmonization which includes use of field-wide benchmarks, harmonization guidelines, and external quality control can support the context-specific evolution of immune assays. Multi-center studies pose particular challenges to sample logistics and quality control of sample specimens. Cooperative groups need to define if immune assessments should be performed in one central facility, in peripheral labs or including a combination of both. Finally, engineered reference samples that contain a defined number of antigen-specific T cells may become broadly applicable tools to control assay performance over time or across institutions.

Evaluating Risks of Insertional Mutagenesis by DNA Transposons in Gene Therapy

Science.gov (United States)

Hackett, Perry B.; Largaespada, David A.; Switzer, Kirsten C.; Cooper, Laurence J.N.

2013-01-01

Investigational therapy can be successfully undertaken using viral- and non-viral-mediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity. We discuss the context in which the SB system can be harnessed for gene therapy and describe the human application of SB-modified CAR+ T cells. We have focused on theoretical issues relating to insertional mutagenesis in the context of human genomes that are naturally subjected to remobilization of transposons and the experimental evidence over the last decade of employing SB transposons for defining genes that induce cancer. These findings are put into the context of the use of SB transposons in the treatment of human disease. PMID:23313630

Ethical issues of perinatal human gene therapy.

Science.gov (United States)

Fletcher, J C; Richter, G

1996-01-01

This paper examines some key ethical issues raised by trials of human gene therapy in the perinatal period--i.e., in infants, young children, and the human fetus. It describes five resources in ethics for researchers' considerations prior to such trials: (1) the history of ethical debate about gene therapy, (2) a literature on the relevance of major ethical principles for clinical research, (3) a body of widely accepted norms and practices, (4) knowledge of paradigm cases, and (5) researchers' own professional integrity. The paper also examines ethical concerns that must be met prior to any trial: benefits to and safety of subjects, informed assent of children and informed parental permission, informed consent of pregnant women in fetal gene therapy, protection of privacy, and concerns about fairness in the selection of subjects. The paper criticizes the position that cases of fetal gene therapy should be restricted only to those where the pregnant woman has explicitly refused abortion. Additional topics include concerns about genetic enhancement and germ-line gene therapy.

Cavitation-enhanced MR-guided focused ultrasound ablation of rabbit tumors in vivo using phase shift nanoemulsions

Science.gov (United States)

Kopechek, Jonathan A.; Park, Eun-Joo; Zhang, Yong-Zhi; Vykhodtseva, Natalia I.; McDannold, Nathan J.; Porter, Tyrone M.

2014-07-01

Advanced tumors are often inoperable due to their size and proximity to critical vascular structures. High intensity focused ultrasound (HIFU) has been developed to non-invasively thermally ablate inoperable solid tumors. However, the clinical feasibility of HIFU ablation therapy has been limited by the long treatment times (on the order of hours) and high acoustic intensities required. Studies have shown that inertial cavitation can enhance HIFU-mediated heating by generating broadband acoustic emissions that increase tissue absorption and accelerate HIFU-induced heating. Unfortunately, initiating inertial cavitation in tumors requires high intensities and can be unpredictable. To address this need, phase-shift nanoemulsions (PSNE) have been developed. PSNE consist of lipid-coated liquid perfluorocarbon droplets that are less than 200 nm in diameter, thereby allowing passive accumulation in tumors through leaky tumor vasculature. PSNE can be vaporized into microbubbles in tumors in order to nucleate cavitation activity and enhance HIFU-mediated heating. In this study, MR-guided HIFU treatments were performed on intramuscular rabbit VX2 tumors in vivo to assess the effect of vaporized PSNE on acoustic cavitation and HIFU-mediated heating. HIFU pulses were delivered for 30 s using a 1.5 MHz, MR-compatible transducer, and cavitation emissions were recorded with a 650 kHz ring hydrophone while temperature was monitored using MR thermometry. Cavitation emissions were significantly higher (P cavitation which correlates with enhanced HIFU-mediated heating in tumors. This suggests that PSNE could potentially be used to reduce the time and/or acoustic intensity required for HIFU-mediated heating, thereby increasing the feasibility and clinical efficacy of HIFU thermal ablation therapy.

Gene therapy, early promises, subsequent problems, and recent breakthroughs.

Science.gov (United States)

Razi Soofiyani, Saeideh; Baradaran, Behzad; Lotfipour, Farzaneh; Kazemi, Tohid; Mohammadnejad, Leila

2013-01-01

Gene therapy is one of the most attractive fields in medicine. The concept of gene delivery to tissues for clinical applications has been discussed around half a century, but scientist's ability to manipulate genetic material via recombinant DNA technology made this purpose to reality. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. While gene therapy initially conceived as a way to treat life-threatening disorders (inborn errors, cancers) refractory to conventional treatment, to date gene therapy is considered for many non-life-threatening conditions including those adversely influence on a patient's quality of life. Gene therapy has made significant progress, including tangible success, although much slower than was initially predicted. Although, gene therapies still at a fairly primitive stage, it is firmly science based. There is justifiable hope that with enhanced pathobiological understanding and biotechnological improvements, gene therapy will be a standard part of clinical practice within 20 years.

Gene delivery to the lungs: pulmonary gene therapy for cystic fibrosis.

Science.gov (United States)

Villate-Beitia, Ilia; Zarate, Jon; Puras, Gustavo; Pedraz, José Luis

2017-07-01

Cystic fibrosis (CF) is a monogenic autosomal recessive disorder where the defective gene, the cystic fibrosis transmembrane conductance regulator (CFTR), is well identified. Moreover, the respiratory tract can be targeted through noninvasive aerosolized formulations for inhalation. Therefore, gene therapy is considered a plausible strategy to address this disease. Conventional gene therapy strategies rely on the addition of a correct copy of the CFTR gene into affected cells in order to restore the channel activity. In recent years, genome correction strategies have emerged, such as zinc-finger nucleases, transcription activator-like effector nucleases and clustered regularly interspaced short palindromic repeats associated to Cas9 nucleases. These gene editing tools aim to repair the mutated gene at its original genomic locus with high specificity. Besides, the success of gene therapy critically depends on the nucleic acids carriers. To date, several clinical studies have been carried out to add corrected copies of the CFTR gene into target cells using viral and non-viral vectors, some of them with encouraging results. Regarding genome editing systems, preliminary in vitro studies have been performed in order to repair the CFTR gene. In this review, after briefly introducing the basis of CF, we discuss the up-to-date gene therapy strategies to address the disease. The review focuses on the main factors to take into consideration when developing gene delivery strategies, such as the design of vectors and plasmid DNA, in vitro/in vivo tests, translation to human use, administration methods, manufacturing conditions and regulatory issues.

Gene therapy for sickle cell disease: An update.

Science.gov (United States)

Demirci, Selami; Uchida, Naoya; Tisdale, John F

2018-05-30

Sickle cell disease (SCD) is one of the most common life-threatening monogenic diseases affecting millions of people worldwide. Allogenic hematopietic stem cell transplantation is the only known cure for the disease with high success rates, but the limited availability of matched sibling donors and the high risk of transplantation-related side effects force the scientific community to envision additional therapies. Ex vivo gene therapy through globin gene addition has been investigated extensively and is currently being tested in clinical trials that have begun reporting encouraging data. Recent improvements in our understanding of the molecular pathways controlling mammalian erythropoiesis and globin switching offer new and exciting therapeutic options. Rapid and substantial advances in genome engineering tools, particularly CRISPR/Cas9, have raised the possibility of genetic correction in induced pluripotent stem cells as well as patient-derived hematopoietic stem and progenitor cells. However, these techniques are still in their infancy, and safety/efficacy issues remain that must be addressed before translating these promising techniques into clinical practice. Published by Elsevier Inc.

Gene Therapy Approaches to Hemoglobinopathies.

Science.gov (United States)

Ferrari, Giuliana; Cavazzana, Marina; Mavilio, Fulvio

2017-10-01

Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with a lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Preclinical and early clinical studies showed the safety and potential efficacy of this therapeutic approach as well as the hurdles still limiting its general application. In addition, for both beta-thalassemia and sickle cell disease, an altered bone marrow microenvironment reduces the efficiency of stem cell harvesting as well as engraftment. These hurdles need be addressed for gene therapy for hemoglobinopathies to become a clinical reality. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene therapy: light is finally in the tunnel.

Science.gov (United States)

Cao, Huibi; Molday, Robert S; Hu, Jim

2011-12-01

After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber's congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

Biodegradable nanoparticles for gene therapy technology

International Nuclear Information System (INIS)

Hosseinkhani, Hossein; He, Wen-Jie; Chiang, Chiao-Hsi; Hong, Po-Da; Yu, Dah-Shyong; Domb, Abraham J.; Ou, Keng-Liang

2013-01-01

Rapid propagations in materials technology together with biology have initiated great hopes in the possibility of treating many diseases by gene therapy technology. Viral and non-viral gene carriers are currently applied for gene delivery. Non-viral technology is safe and effective for the delivery of genetic materials to cells and tissues. Non-viral systems are based on plasmid expression containing a gene encoding a therapeutic protein and synthetic biodegradable nanoparticles as a safe carrier of gene. Biodegradable nanoparticles have shown great interest in drug and gene delivery systems as they are easy to be synthesized and have no side effect in cells and tissues. This review provides a critical view of applications of biodegradable nanoparticles on gene therapy technology to enhance the localization of in vitro and in vivo and improve the function of administered genes

Human gene therapy: novel approaches to improve the current gene delivery systems.

Science.gov (United States)

Cucchiarini, Magali

2016-06-01

Even though gene therapy made its way through the clinics to treat a number of human pathologies since the early years of experimental research and despite the recent approval of the first gene-based product (Glybera) in Europe, the safe and effective use of gene transfer vectors remains a challenge in human gene therapy due to the existence of barriers in the host organism. While work is under active investigation to improve the gene transfer systems themselves, the use of controlled release approaches may offer alternative, convenient tools of vector delivery to achieve a performant gene transfer in vivo while overcoming the various physiological barriers that preclude its wide use in patients. This article provides an overview of the most significant contributions showing how the principles of controlled release strategies may be adapted for human gene therapy.

Improving the Safety of Cell Therapy Products by Suicide Gene Transfer

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Antonio eDi Stasi

2014-11-01

Full Text Available Adoptive T-cell therapy can involve donor lymphocyte infusion (DLI after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte (TILs expanded ex-vivo, or more recently the use of T cell receptor (TCR or chimeric antigen receptor (CAR redirected T cells. However cellular therapies can pose significant risks, including graft-versus-host-disease and other on and off-target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene-modified cells, preventing collateral damage to contiguous cells and/or tissues. The ‘ideal’ suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of ‘all’ and ‘only’ the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase (HSV-TK and inducible-caspase-9 (iCasp9.

Simian virus 40 vectors for pulmonary gene therapy

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Oppenheim Ariella

2007-10-01

Full Text Available Abstract Background Sepsis remains the leading cause of death in critically ill patients. One of the primary organs affected by sepsis is the lung, presenting as the Acute Respiratory Distress Syndrome (ARDS. Organ damage in sepsis involves an alteration in gene expression, making gene transfer a potential therapeutic modality. This work examines the feasibility of applying simian virus 40 (SV40 vectors for pulmonary gene therapy. Methods Sepsis-induced ARDS was established by cecal ligation double puncture (2CLP. SV40 vectors carrying the luciferase reporter gene (SV/luc were administered intratracheally immediately after sepsis induction. Sham operated (SO as well as 2CLP rats given intratracheal PBS or adenovirus expressing luciferase served as controls. Luc transduction was evaluated by in vivo light detection, immunoassay and luciferase mRNA detection by RT-PCR in tissue harvested from septic rats. Vector abundance and distribution into alveolar cells was evaluated using immunostaining for the SV40 VP1 capsid protein as well as by double staining for VP1 and for the surfactant protein C (proSP-C. Immunostaining for T-lymphocytes was used to evaluate the cellular immune response induced by the vector. Results Luc expression measured by in vivo light detection correlated with immunoassay from lung tissue harvested from the same rats. Moreover, our results showed vector presence in type II alveolar cells. The vector did not induce significant cellular immune response. Conclusion In the present study we have demonstrated efficient uptake and expression of an SV40 vector in the lungs of animals with sepsis-induced ARDS. These vectors appear to be capable of in vivo transduction of alveolar type II cells and may thus become a future therapeutic tool.

Gene Therapy, Early Promises, Subsequent Problems, and Recent Breakthroughs

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Saeideh Razi Soofiyani

2013-08-01

Full Text Available Gene therapy is one of the most attractive fields in medicine. The concept of gene delivery to tissues for clinical applications has been discussed around half a century, but scientist’s ability to manipulate genetic material via recombinant DNA technology made this purpose to reality. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. While gene therapy initially conceived as a way to treat life-threatening disorders (inborn errors, cancers refractory to conventional treatment, to date gene therapy is considered for many non–life-threatening conditions including those adversely influence on a patient’s quality of life. Gene therapy has made significant progress, including tangible success, although much slower than was initially predicted. Although, gene therapies still at a fairly primitive stage, it is firmly science based. There is justifiable hope that with enhanced pathobiological understanding and biotechnological improvements, gene therapy will be a standard part of clinical practice within 20 years.

Newer Gene Editing Technologies toward HIV Gene Therapy

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Premlata Shankar

2013-11-01

Full Text Available Despite the great success of highly active antiretroviral therapy (HAART in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.

Twenty Years of European Union Support to Gene Therapy and Gene Transfer.

Science.gov (United States)

Gancberg, David

2017-11-01

For 20 years and throughout its research programmes, the European Union has supported the entire innovation chain for gene transfer and gene therapy. The fruits of this investment are ripening as gene therapy products are reaching the European market and as clinical trials are demonstrating the safety of this approach to treat previously untreatable diseases.

Progress toward Gene Therapy for Duchenne Muscular Dystrophy.

Science.gov (United States)

Chamberlain, Joel R; Chamberlain, Jeffrey S

2017-05-03

Duchenne muscular dystrophy (DMD) has been a major target for gene therapy development for nearly 30 years. DMD is among the most common genetic diseases, and isolation of the defective gene (DMD, or dystrophin) was a landmark discovery, as it was the first time a human disease gene had been cloned without knowledge of the protein product. Despite tremendous obstacles, including the enormous size of the gene and the large volume of muscle tissue in the human body, efforts to devise a treatment based on gene replacement have advanced steadily through the combined efforts of dozens of labs and patient advocacy groups. Progress in the development of DMD gene therapy has been well documented in Molecular Therapy over the past 20 years and will be reviewed here to highlight prospects for success in the imminent human clinical trials planned by several groups. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Dual AAV Gene Therapy for Duchenne Muscular Dystrophy with a 7-kb Mini-Dystrophin Gene in the Canine Model.

Science.gov (United States)

Kodippili, Kasun; Hakim, Chady H; Pan, Xiufang; Yang, Hsiao T; Yue, Yongping; Zhang, Yadong; Shin, Jin-Hong; Yang, N Nora; Duan, Dongsheng

2018-03-01

Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof of principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ΔH2-R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ΔH2-R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy. We packaged minigene dual vectors in Y731F tyrosine-modified AAV-9 and delivered to the extensor carpi ulnaris muscle of a 12-month-old affected dog at the dose of 2 × 10 13 viral genome particles/vector/muscle. Widespread mini-dystrophin expression was observed 2 months after gene transfer. The missing dystrophin-associated glycoprotein complex was restored. Treatment also reduced muscle degeneration and fibrosis and improved myofiber size distribution. Importantly, dual AAV therapy greatly protected the muscle from eccentric contraction-induced force loss. Our data provide the first clear evidence that dual AAV therapy can be translated to a diseased large mammal. Further development of dual AAV technology may lead to effective therapies for DMD and many other diseases in human patients.

Gene therapy for carcinoma of the breast: Genetic toxins

International Nuclear Information System (INIS)

Vassaux, Georges; Lemoine, Nick R

2000-01-01

Gene therapy was initially envisaged as a potential treatment for genetically inherited, monogenic disorders. The applications of gene therapy have now become wider, however, and include cardiovascular diseases, vaccination and cancers in which conventional therapies have failed. With regard to oncology, various gene therapy approaches have been developed. Among them, the use of genetic toxins to kill cancer cells selectively is emerging. Two different types of genetic toxins have been developed so far: the metabolic toxins and the dominant-negative class of toxins. This review describes these two different approaches, and discusses their potential applications in cancer gene therapy

A novel double-enhanced suicide gene therapy in a colon cancer cell line mediated by gef and apoptin.

Science.gov (United States)

Boulaiz, Houria; Aránega, Antonia; Cáceres, Blanca; Blanca, Cáceres; Alvarez, Pablo; Pablo, Alvarez; Serrano-Rodríguez, Fernando; Fernando, Rodríguez-Serrano; Carrillo, Esmeralda; Esmeralda, Carrillo; Melguizo, Consolación; Consolación, Melguizo; Prados, Jose; Jose, Prados

2014-02-01

Double-suicide gene therapy is a promising strategy for the treatment of advanced cancer. It has become an important research line in the development of gene therapy to overcome the drawbacks of single-gene therapy. The aim of this study was to investigate the usefulness of double-suicide gene therapy with the two suicide genes, gef and apoptin, in colon carcinoma. gef and apoptin genes were cloned into a doxycycline-regulated retrovirus-mediated gene expression system. Expression of both genes in the DLD-1 cell line was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR). Cell viability was determined with the sulforhodamine B colorimetric assay, and the cell cycle was studied by propidium iodide (PI) staining. Annexin V-FITC and PI assays were used to evaluate apoptosis, and the results were confirmed by electron microscopy. The mitochondrial membrane potential was measured by JC-1 assay. Our results showed that the combined expression of gef and apoptin genes was strikingly more effective than the expression of either gene alone. Co-expression of gef and apoptin synergistically enhanced the decrease in cell viability, increasing necrosis and inducing apoptosis in colon cancer cells via the mitochondrial pathway, which can be deficient in advanced or metastatic colon cancer. Double-suicide gene therapy based on gef and apoptin genes may be a candidate for the development of new colon cancer strategies, and further studies are warranted to establish the usefulness of double-suicide gene therapy in vivo.

OFFICIAL MEDICATIONS FOR ANTI-TUMOR GENE THERAPY

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E. R. Nemtsova

2016-01-01

Full Text Available This is a review of modern literature data of official medications for anti-tumor gene therapy as well as of medications that finished clinical trials.The article discusses the concept of gene therapy, the statistical analysis results of initiated clinical trials of gene products, the most actively developing directions of anticancer gene therapy, and the characteristics of anti-tumor gene medications.Various delivery systems for gene material are being examined, including viruses that are defective in  replication (Gendicine™ and Advexin and oncolytic (tumor specific conditionally replicating viruses (Oncorine™, ONYX-015, Imlygic®.By now three preparations for intra-tumor injection have been introduced into oncology clinical practice: two of them – Gendicine™ and Oncorine™ have been registered in China, and one of them – Imlygic® has been registered in the USA. Gendicine™ and Oncorine™ are based on the wild type p53 gene and are designed for treatment of patients with head and neck malignancies. Replicating adenovirus is the delivery system in Gendicine™, whereas oncolytic adenovirus is the vector for gene material in Oncorine™. Imlygic® is based on the  recombinant replicating HSV1 virus with an introduced GM–CSF gene and is designed for treatment of  melanoma patients. These medications are well tolerated and do not cause any serious adverse events. Gendicine™ and Oncorine™ are not effective in monotherapy but demonstrate pronounced synergism with chemoand radiation therapy. Imlygic® has just started the post marketing trials.

Insulin gene therapy for type 1 diabetes mellitus.

Science.gov (United States)

Handorf, Andrew M; Sollinger, Hans W; Alam, Tausif

2015-04-01

Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or whole pancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.

Approach of combined cancer gene therapy and radiation: response of promoters to ionizing radiation; Approche de therapie genique anti-cancereuse combinee a l'irradiation: etude de la reponse de promoteurs aux radiations ionisantes

Energy Technology Data Exchange (ETDEWEB)

Anstett, A

2005-09-15

Gene therapy is an emerging cancer treatment modality. We are interested in developing a radiation-inducible gene therapy system to sensitize the tumor vasculature to the effects of ionizing radiation (IR) treatment. An expression system based on irradiation-inducible promoters will drive the expression of anti-tumor genes in the tumor vasculature. Solid tumors are dependent on angio genesis, a process in which new blood vessels are formed from the pre-existing vasculature. Vascular endothelial cells are un transformed and genetically stable, thus avoiding the problem of resistance to the treatments. Vascular endothelial cells may therefore represent a suitable target for this therapeutic gene therapy strategy.The identification of IR-inducible promoters native to endothelial cells was performed by gene expression profiling using cDNA micro array technology. We describe the genes modified by clinically relevant doses of IR. The extension to high doses aimed at studying the effects of total radiation delivery to the tumor. The radio-inductiveness of the genes selected for promoter study was confirmed by RT-PCR. Analysis of the activity of promoters in response to IR was also assessed in a reporter plasmid. We found that authentic promoters cloned onto a plasmid are not suitable for cancer gene therapy due to their low induction after IR. In contrast, synthetic promoters containing repeated sequence-specific binding sites for IR-activated transcription factors such as NF-{kappa}B are potential candidates for gene therapy. The activity of five tandemly repeated TGGGGACTTTCCGC elements for NF-{kappa}B binding in a luciferase reporter was increased in a dose-dependent manner. Interestingly, the response to fractionated low doses was improved in comparison to the total single dose. Thus, we put present evidence that a synthetic promoter for NF-{kappa}B specific binding may have application in the radio-therapeutic treatment of cancer. (author)

HIFU scattering by the ribs: constrained optimisation with a complex surface impedance boundary condition

Science.gov (United States)

Gélat, P.; ter Haar, G.; Saffari, N.

2014-04-01

High intensity focused ultrasound (HIFU) enables highly localised, non-invasive tissue ablation and its efficacy has been demonstrated in the treatment of a range of cancers, including those of the kidney, prostate and breast. HIFU offers the ability to treat deep-seated tumours locally, and potentially bears fewer side effects than more established treatment modalities such as resection, chemotherapy and ionising radiation. There remains however a number of significant challenges which currently hinder its widespread clinical application. One of these challenges is the need to transmit sufficient energy through the ribcage to ablate tissue at the required foci whilst minimising the formation of side lobes and sparing healthy tissue. Ribs both absorb and reflect ultrasound strongly. This sometimes results in overheating of bone and overlying tissue during treatment, leading to skin burns. Successful treatment of a patient with tumours in the upper abdomen therefore requires a thorough understanding of the way acoustic and thermal energy is deposited. Previously, a boundary element (BE) approach based on a Generalised Minimal Residual (GMRES) implementation of the Burton-Miller formulation was developed to predict the field of a multi-element HIFU array scattered by human ribs, the topology of which was obtained from CT scan data [1]. Dissipative mechanisms inside the propagating medium have since been implemented, together with a complex surface impedance condition at the surface of the ribs. A reformulation of the boundary element equations as a constrained optimisation problem was carried out to determine the complex surface velocities of a multi-element HIFU array which generated the acoustic pressure field that best fitted a required acoustic pressure distribution in a least-squares sense. This was done whilst ensuring that an acoustic dose rate parameter at the surface of the ribs was kept below a specified threshold. The methodology was tested at an

Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

Science.gov (United States)

2015-01-01

Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

In vitro and in vivo gene therapy with CMV vector-mediated presumed dog beta-nerve growth factor in pyridoxine-induced neuropathy dogs.

Science.gov (United States)

Chung, Jin Young; Choi, Jung Hoon; Shin, Il Seob; Choi, Eun Wha; Hwang, Cheol Yong; Lee, Sang Koo; Youn, Hwa Young

2008-12-01

Due to the therapeutic potential of gene therapy for neuronal injury, many studies of neurotrophic factors, vectors, and animal models have been performed. The presumed dog beta-nerve growth factor (pdbeta-NGF) was generated and cloned and its expression was confirmed in CHO cells. The recombinant pdbeta-NGF protein reacted with a human beta-NGF antibody and showed bioactivity in PC12 cells. The pdbeta-NGF was shown to have similar bioactivity to the dog beta-NGF. The recombinant pdbeta-NGF plasmid was administrated into the intrathecal space in the gene therapy group. Twenty-four hours after the vector inoculation, the gene therapy group and the positive control group were intoxicated with excess pyridoxine for seven days. Each morning throughout the test period, the dogs' body weight was taken and postural reaction assessments were made. Electrophysiological recordings were performed twice, once before the experiment and once after the test period. After the experimental period, histological analysis was performed. Dogs in the gene therapy group had no weight change and were normal in postural reaction assessments. Electrophysiological recordings were also normal for the gene therapy group. Histological analysis showed that neither the axons nor the myelin of the dorsal funiculus of L4 were severely damaged in the gene therapy group. In addition, the dorsal root ganglia of L4 and the peripheral nerves (sciatic nerve) did not experience severe degenerative changes in the gene therapy group. This study is the first to show the protective effect of NGF gene therapy in a dog model.

Sjogren Syndrome-Gene Therapy and its Prospective

Directory of Open Access Journals (Sweden)

R Rahpeyma

2003-02-01

Full Text Available Sjogren syndrome is one of the autoimmune diseases which is characterized by lymphocytic infiltration to exocrine glands and causes keratoconjunctivitis sicca and xerostomia. Today, a large population, with a majority of women over 40, suffer from this disease and have several complications regarding oral health and reduced life quality such as severe dental caries, painful eyes, olfactory and gustatory deficiency, speech, mastication and swallowing discomforts. Unfortunately, these patients do not respond to the conventional therapies. Nowadays in medical world, which its target is basic therapy and not symptomatic one, several gene therapy approaches, have gained importance in treatment of this apparently incurable diseases. Due to the facts that this disease is the second prevelant autoimmune disease, after rheumatoid arthritis, and the conventional therapies of the disease are all relative and symptomatic, researchers have insisted on the basic and causative therapy through gene transfer more than before. In the Present article, through reviewing 58 references containing recent scientific and investigatory findings it has been tried, to consider the pathogenesis and conventional therapies of this syndrome. Another purpose of this study was to investigate several and potentially very effective gene transfer systems and different theraputic genes (mainly membrane water channels, ione transporter molecules, transcription factors, antifungal proteins and free radical scavengers.

Beta-Adrenergic gene therapy for cardiovascular disease

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Koch Walter J

2000-10-01

Full Text Available Abstract Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct, acting as a Gβγ-β-adrenergic receptor kinase (βARK1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, βARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of βARK1 activity and sequestration of Gβγ via an adenovirus that encodes the βARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.

Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors

International Nuclear Information System (INIS)

Ahmed, M.

2003-01-01

Ionizing radiation exposure is associated with activation of certain immediate-early genes that function as transcription factors. These include members of jun or fos and early growth response (EGR) gene families. In particular, the functional role of EGR-1 in radiation-induced signaling is pivotal since the promoter of EGR-1 contains radiation-inducible CArG DNA sequences. The Egr-1 gene belongs to a family of Egr genes that includes EGR-2, EGR-3, EGR-4, EGR-α and the tumor suppressor, Wilms' tumor gene product, WT1. The Egr-1 gene product, EGR-1, is a nuclear protein that contains three zinc fingers of the C 2 H 2 subtype. The EGR-1 GC-rich consensus target sequence, 5'-GCGT/GGGGCG-3' or 5'-TCCT/ACCTCCTCC-3', has been identified in the promoter regions of transcription factors, growth factors, receptors, cell cycle regulators and pro-apoptotic genes. The gene targets mediated by Egr-1 in response to ionizing radiation include TNF-α , p53, Rb and Bax, all these are effectors of apoptosis. Based on these targets, Egr-1 is a pivotal gene that initiates early signal transduction events in response to ionizing radiation leading to either growth arrest or cell death in tumor cells. There are two potential application of Egr-1 gene in therapy of cancer. First, the Egr-1 promoter contains information for appropriate spatial and temporal expression in-vivo that can be regulated by ionizing radiation to control transcription of genes that have pro-apoptotic and suicidal function. Secondly, EGR-1 protein can eliminate 'induced-radiation resistance' by inhibiting the functions of radiation-induced pro-survival genes (NFκB activity and bcl-2 expression) and activate pro-apoptotic genes (such as bax) to confer a significant radio-sensitizing effect. Together, the reported findings from my laboratory demonstrate clearly that EGR-1 is an early central gene that confers radiation sensitivity and its pro-apoptotic functions are synergized by abrogation of induced radiation

A Comprehensive Review of Retinal Gene Therapy

OpenAIRE

Boye, Shannon E; Boye, Sanford L; Lewin, Alfred S; Hauswirth, William W

2013-01-01

Blindness, although not life threatening, is a debilitating disorder for which few, if any treatments exist. Ocular gene therapies have the potential to profoundly improve the quality of life in patients with inherited retinal disease. As such, tremendous focus has been given to develop such therapies. Several factors make the eye an ideal organ for gene-replacement therapy including its accessibility, immune privilege, small size, compartmentalization, and the existence of a contralateral co...

AAV2-mediated in vivo immune gene therapy of solid tumours

LENUS (Irish Health Repository)

Collins, Sara A

2010-12-20

Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb\\/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour

Targeted cytosine deaminase-uracil phosphoribosyl transferase suicide gene therapy induces small cell lung cancer-specific cytotoxicity and tumor growth delay

DEFF Research Database (Denmark)

Christensen, Camilla L; Gjetting, Torben; Poulsen, Thomas Tuxen

2010-01-01

Small cell lung cancer (SCLC) is a highly malignant cancer for which there is no curable treatment. Novel therapies are therefore in great demand. In the present study we investigated the therapeutic effect of transcriptionally targeted suicide gene therapy for SCLC based on the yeast cytosine...... deaminase (YCD) gene alone or fused with the yeast uracil phosphoribosyl transferase (YUPRT) gene followed by administration of 5-fluorocytosine (5-FC) prodrug. Experimental design: The YCD gene or the YCD-YUPRT gene was placed under regulation of the SCLC-specific promoter insulinoma-associated 1 (INSM1...

On the scientific and ethical issues of fetal somatic gene therapy.

Science.gov (United States)

Coutelle, C; Rodeck, C

2002-06-01

Fetal somatic gene therapy is often seen as an ethically particularly controversial field of gene therapy. This review outlines the hypothesis and scientific background of in utero gene therapy and addresses some of the frequently raised questions and concerns in relation to this still experimental, potentially preventive gene therapy approach. We discuss here the choice of vectors, of animal models and routes of administration to the fetus. We address the relation of fetal gene therapy to abortion, to post-implantation selection and postnatal gene therapy and the concerns of inadvertent germ-line modification. Our views on the specific risks of prenatal gene therapy and on the particular prerequisites that have to be met before human application can be considered are presented.

Thermal and mechanical high-intensity focused ultrasound: perspectives on tumor ablation, immune effects and combination strategies.

Science.gov (United States)

van den Bijgaart, Renske J E; Eikelenboom, Dylan C; Hoogenboom, Martijn; Fütterer, Jurgen J; den Brok, Martijn H; Adema, Gosse J

2017-02-01

Tumor ablation technologies, such as radiofrequency-, cryo- or high-intensity focused ultrasound (HIFU) ablation will destroy tumor tissue in a minimally invasive manner. Ablation generates large volumes of tumor debris in situ, releasing multiple bio-molecules like tumor antigens and damage-associated molecular patterns. To initiate an adaptive antitumor immune response, antigen-presenting cells need to take up tumor antigens and, following activation, present them to immune effector cells. The impact of the type of tumor ablation on the precise nature, availability and suitability of the tumor debris for immune response induction, however, is poorly understood. In this review, we focus on immune effects after HIFU-mediated ablation and compare these to findings using other ablation technologies. HIFU can be used both for thermal and mechanical destruction of tissue, inducing coagulative necrosis or subcellular fragmentation, respectively. Preclinical and clinical results of HIFU tumor ablation show increased infiltration and activation of CD4 + and CD8 + T cells. As previously observed for other types of tumor ablation technologies, however, this ablation-induced enhanced infiltration alone appears insufficient to generate consistent protective antitumor immunity. Therapies combining ablation with immune stimulation are therefore expected to be key to boost HIFU-induced immune effects and to achieve systemic, long-lasting, antitumor immunity.

Theranostic Imaging of Cancer Gene Therapy.

Science.gov (United States)

Sekar, Thillai V; Paulmurugan, Ramasamy

2016-01-01

Gene-directed enzyme prodrug therapy (GDEPT) is a promising therapeutic approach for treating cancers of various phenotypes. This strategy is independent of various other chemotherapeutic drugs used for treating cancers where the drugs are mainly designed to target endogenous cellular mechanisms, which are different in various cancer subtypes. In GDEPT an external enzyme, which is different from the cellular proteins, is expressed to convert the injected prodrug in to a toxic metabolite, that normally kill cancer cells express this protein. Theranostic imaging is an approach used to directly monitor the expression of these gene therapy enzymes while evaluating therapeutic effect. We recently developed a dual-GDEPT system where we combined mutant human herpes simplex thymidine kinase (HSV1sr39TK) and E. coli nitroreductase (NTR) enzyme, to improve therapeutic efficiency of cancer gene therapy by simultaneously injecting two prodrugs at a lower dose. In this approach we use two different prodrugs such as ganciclovir (GCV) and CB1954 to target two different cellular mechanisms to kill cancer cells. The developed dual GDEPT system was highly efficacious than that of either of the system used independently. In this chapter, we describe the complete protocol involved for in vitro and in vivo imaging of therapeutic cancer gene therapy evaluation.

Approach of combined cancer gene therapy and radiation: response of promoters to ionizing radiation; Approche de therapie genique anti-cancereuse combinee a l'irradiation: etude de la reponse de promoteurs aux radiations ionisantes

Energy Technology Data Exchange (ETDEWEB)

Anstett, A

2005-09-15

Gene therapy is an emerging cancer treatment modality. We are interested in developing a radiation-inducible gene therapy system to sensitize the tumor vasculature to the effects of ionizing radiation (IR) treatment. An expression system based on irradiation-inducible promoters will drive the expression of anti-tumor genes in the tumor vasculature. Solid tumors are dependent on angio genesis, a process in which new blood vessels are formed from the pre-existing vasculature. Vascular endothelial cells are un transformed and genetically stable, thus avoiding the problem of resistance to the treatments. Vascular endothelial cells may therefore represent a suitable target for this therapeutic gene therapy strategy.The identification of IR-inducible promoters native to endothelial cells was performed by gene expression profiling using cDNA micro array technology. We describe the genes modified by clinically relevant doses of IR. The extension to high doses aimed at studying the effects of total radiation delivery to the tumor. The radio-inductiveness of the genes selected for promoter study was confirmed by RT-PCR. Analysis of the activity of promoters in response to IR was also assessed in a reporter plasmid. We found that authentic promoters cloned onto a plasmid are not suitable for cancer gene therapy due to their low induction after IR. In contrast, synthetic promoters containing repeated sequence-specific binding sites for IR-activated transcription factors such as NF-{kappa}B are potential candidates for gene therapy. The activity of five tandemly repeated TGGGGACTTTCCGC elements for NF-{kappa}B binding in a luciferase reporter was increased in a dose-dependent manner. Interestingly, the response to fractionated low doses was improved in comparison to the total single dose. Thus, we put present evidence that a synthetic promoter for NF-{kappa}B specific binding may have application in the radio-therapeutic treatment of cancer. (author)

Numerical Study for Optimizing Parameters of High-Intensity Focused Ultrasound-Induced Thermal Field during Liver Tumor Ablation: HIFU Simulator

Directory of Open Access Journals (Sweden)

Somayeh gharloghi

2017-03-01

Full Text Available Introduction High intensity focused ultrasound (HIFU is considered a noninvasive and effective technique for tumor ablation. Frequency and acoustic power are the most effective parameters for temperature distribution and the extent of tissue damage. The aim of this study was to optimize the operating transducer parameters such as frequency and input power in order to acquire suitable temperature and thermal dose distribution in the course of a numerical assessment. Materials and Methods To model the sound propagation, the Khokhlov-Zabolotskava-Kuznetsov (KZK nonlinear wave equation was used and simulation was carried out using MATLAB HIFU toolbox. Bioheat equation was applied to calculate the transient temperature in the liver tissue. Frequency ranges of 2, 3, 4, and 5 MHz and power levels of 50 and 100 W were applied using an extracorporeal transducer. Results Using a frequency of 2 MHz, the maximum temperatures reached 53°C and 90°C in the focal point for power levels of 50 W and 100 W, respectively. With the same powers and using a frequency of 3 MHz, the temperature reached to 71°C and 170°C, respectively. In addition, for these power levels at the frequency of 4 MHz, the temperature reached to 72°C and 145°C, respectively. However, at the 5 MHz frequency, the temperature in the focal spot was either 57°C or 79°C. Conclusion Use of frequency of 2 MHz and power of 100 W led to higher thermal dose distribution, and subsequently, reduction of the treatment duration and complications at the same exposure time in ablation of large tumors.

In vivo PET imaging with 18F-FHBG of hepatoma cancer gene therapy using herpes simplex virus thymidine kinase and ganciclovir

International Nuclear Information System (INIS)

Lee, TaeSup; Kim, JunYoup; Moon, ByungSeok; Kang, JooHyun; Song, Inho; Kwon, HeeChung; Kim, KyungMin; Cheon, GiJeong; Choi, ChangWoon; Lim, SangMoo

2007-01-01

Monitoring gene expression in vivo to evaluate the gene therapy efficacy is a critical issue for scientists and physicians. Non-invasive nuclear imaging can offer information regarding the level of gene expression and its location when an appropriate reporter gene is constructed in the therapeutic gene therapy. Herpes simplex virus type 1 thymidine kinase gene (HSV1-tk) is the most common reporter gene and is used in cancer gene therapy by activating relatively nontoxic compounds, such as acyclovir or ganciclovir (GCV), to induce cell death. In this study, we investigate the feasibility of monitoring cancer gene therapy using retroviral vector transduced HSV1-tk and GCV, in vitro cellular uptake and in vivo animal studies, including biodistribution and small animal positron emission tomography (PET) imaging, were performed in HSV1-tk and luciferase (Luc)-transduced MCA-TK/Luc and enhanced green fluorescent protein (eGFP)-transduced MCA-eGFP hepatoma cell lines

Adeno-associated virus LPL(S447X) gene therapy in LDL receptor knockout mice

NARCIS (Netherlands)

Rip, Jaap; Sierts, Jeroen A.; Vaessen, Stefan F. C.; Kastelein, John J. P.; Twisk, Jaap; Kuivenhoven, Jan Albert

2007-01-01

BACKGROUND: Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPL(S447X) cDNA to skeletal muscle could induce similar effects. METHODS: LDL receptor knockout (LDLr-/-) mice were

Proton Therapy as Salvage Treatment for Local Relapse of Prostate Cancer Following Cryosurgery or High-Intensity Focused Ultrasound

International Nuclear Information System (INIS)

Holtzman, Adam L.; Hoppe, Bradford S.; Letter, Haley P.; Bryant, Curtis; Nichols, Romaine C.; Henderson, Randal H.; Mendenhall, William M.; Morris, Christopher G.; Williams, Christopher R.; Li, Zuofeng; Mendenhall, Nancy P.

2016-01-01

Purpose: Local recurrence of prostate cancer after cryosurgery (CS) and high-intensity focused ultrasound (HIFU) is an emerging problem for which optimal management is unknown. Proton therapy (PT) may offer advantages over other local therapeutic options. This article reviews a single institution's experience using PT for salvage of local recurrent disease after HIFU or CS. Methods and Materials: We reviewed the medical records of 21 consecutive patients treated with salvage PT following a local recurrence of prostate cancer after CS (n=12) or HIFU (n=9) between January 2007 and July 2014. Patients were treated to a median dose of 74 Gy(relative biological effectiveness [RBE]; range: 74-82 Gy[RBE]) and 8 patients received androgen deprivation therapy with radiation therapy. Patients were evaluated for quality of life (QOL) by using the Expanded Prostate Index Composite questionnaire and toxicity by using Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment, every 6 months for 2 years after treatment, and then annually. Results: Median follow-up was 37 months (range: 6-95 months). The 3-year biochemical progression-free survival (bPFS) rate was 77%. The 3-year grade 3 toxicity rate was 17%; however, 2 of these patients had pre-existing grade 3 GU toxicities from their HIFU/CRYO prior to PT. At 1 year, bowel summary, urinary incontinence, and urinary obstructive QOL scores declined, but only the bowel QOL score at 12 months met the minimally important difference threshold. Conclusions: PT achieved a high rate of bPFS with acceptable toxicity and minimal changes in QOL scores compared with baseline pre-PT functions. Although most patients have done fairly well, the study size is small, follow-up is short, and early results suggest that outcomes with PT for salvage after HIFU or CS failure are inferior to outcomes with PT given in the de novo setting with respect to disease control, toxicity, and QOL.

Proton Therapy as Salvage Treatment for Local Relapse of Prostate Cancer Following Cryosurgery or High-Intensity Focused Ultrasound

Energy Technology Data Exchange (ETDEWEB)

Holtzman, Adam L. [University of Florida Health Proton Therapy Institute, University of Florida College of Medicine, Jacksonville, Florida (United States); Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org [University of Florida Health Proton Therapy Institute, University of Florida College of Medicine, Jacksonville, Florida (United States); Letter, Haley P.; Bryant, Curtis; Nichols, Romaine C.; Henderson, Randal H.; Mendenhall, William M.; Morris, Christopher G. [University of Florida Health Proton Therapy Institute, University of Florida College of Medicine, Jacksonville, Florida (United States); Williams, Christopher R. [Department of Surgery, University of Florida College of Medicine, Jacksonville, Florida (United States); Li, Zuofeng; Mendenhall, Nancy P. [University of Florida Health Proton Therapy Institute, University of Florida College of Medicine, Jacksonville, Florida (United States)

2016-05-01

Purpose: Local recurrence of prostate cancer after cryosurgery (CS) and high-intensity focused ultrasound (HIFU) is an emerging problem for which optimal management is unknown. Proton therapy (PT) may offer advantages over other local therapeutic options. This article reviews a single institution's experience using PT for salvage of local recurrent disease after HIFU or CS. Methods and Materials: We reviewed the medical records of 21 consecutive patients treated with salvage PT following a local recurrence of prostate cancer after CS (n=12) or HIFU (n=9) between January 2007 and July 2014. Patients were treated to a median dose of 74 Gy(relative biological effectiveness [RBE]; range: 74-82 Gy[RBE]) and 8 patients received androgen deprivation therapy with radiation therapy. Patients were evaluated for quality of life (QOL) by using the Expanded Prostate Index Composite questionnaire and toxicity by using Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment, every 6 months for 2 years after treatment, and then annually. Results: Median follow-up was 37 months (range: 6-95 months). The 3-year biochemical progression-free survival (bPFS) rate was 77%. The 3-year grade 3 toxicity rate was 17%; however, 2 of these patients had pre-existing grade 3 GU toxicities from their HIFU/CRYO prior to PT. At 1 year, bowel summary, urinary incontinence, and urinary obstructive QOL scores declined, but only the bowel QOL score at 12 months met the minimally important difference threshold. Conclusions: PT achieved a high rate of bPFS with acceptable toxicity and minimal changes in QOL scores compared with baseline pre-PT functions. Although most patients have done fairly well, the study size is small, follow-up is short, and early results suggest that outcomes with PT for salvage after HIFU or CS failure are inferior to outcomes with PT given in the de novo setting with respect to disease control, toxicity, and QOL.

Bacteria as vectors for gene therapy of cancer.

LENUS (Irish Health Repository)

Baban, Chwanrow K

2012-01-31

Anti-cancer therapy faces major challenges, particularly in terms of specificity of treatment. The ideal therapy would eradicate tumor cells selectively with minimum side effects on normal tissue. Gene or cell therapies have emerged as realistic prospects for the treatment of cancer, and involve the delivery of genetic information to a tumor to facilitate the production of therapeutic proteins. However, there is still much to be done before an efficient and safe gene medicine is achieved, primarily developing the means of targeting genes to tumors safely and efficiently. An emerging family of vectors involves bacteria of various genera. It has been shown that bacteria are naturally capable of homing to tumors when systemically administered resulting in high levels of replication locally. Furthermore, invasive species can deliver heterologous genes intra-cellularly for tumor cell expression. Here, we review the use of bacteria as vehicles for gene therapy of cancer, detailing the mechanisms of action and successes at preclinical and clinical levels.

Germ-line gene therapy and the medical imperative.

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Munson, Ronald; Davis, Lawrence H

1992-06-01

Somatic cell gene therapy has yielded promising results. If germ cell gene therapy can be developed, the promise is even greater: hundreds of genetic diseases might be virtually eliminated. But some claim the procedure is morally unacceptable. We thoroughly and sympathetically examine several possible reasons for this claim but find them inadequate. There is no moral reason, then, not to develop and employ germ-line gene therapy. Taking the offensive, we argue next that medicine has a prima facie moral obligation to do so.

Design of radiopharmaceuticals for monitoring gene transfer therapy

International Nuclear Information System (INIS)

Lambrecht, R.M.; Staehler, P.; Kley, J.; Spiegel, M.; Gross, C.; Graepler, F.T.C.; Gregor, M.; Lauer, U.; Oberdorfer, F.

1998-01-01

The development of radiopharmaceuticals for monitoring gene transfer therapy with emission tomography is expected to lead to improved management of cancer by the year 2010. There are now only a few examples and approaches to the design of radiopharmaceuticals for gene transfer therapy. This paper introduces a novel concept for the monitoring of gene therapy. We present the optimisation of the labelling of recombinant human β-NGF ligands for in vitro studies prior to using 123 I for SPET and 124 I for PET studies. (author)

Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes.

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Rouanet, Marie; Lebrin, Marine; Gross, Fabian; Bournet, Barbara; Cordelier, Pierre; Buscail, Louis

2017-06-08

A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials.

Gene Therapy and its applications in Dentistry

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Sharma Lakhanpal Manisha

2006-01-01

Full Text Available This era of advanced technology is marked by progress in identifying and understanding the molecular and cellular cause of a disease. With the conventional methods of treatment failing to render satisfactory results, gene therapy is not only being used for the cure of inherited diseases but also the acquired ones. The broad spectrum of gene therapy includes its application in the treatment of oral cancer and precancerous conditions and lesions, treatment of salivary gland diseases, bone repair, autoimmune diseases, DNA vaccination, etc. The aim of this article is to throw light on the history, methodology, applications and future of gene therapy as it would change the nature and face of dentistry in the coming years.

Construction Of An Optimized Lentiviral Vector Containing Pdx-1 Gene For Transduction Of Stem Cells Towards Gene Therapy Diabetes Type 1

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S Rahmati

2013-02-01

Full Text Available Abstract Background & aim: Nowadays, most of gene therapy protocols are performed by lentiviral vectors. One of the most important factors which is involved in pancreas development and transcription of insulin gene is pancreatic & duodenal homeobox 1 (PDX-1 transcription factor. The goal of this study was to optimize a lentiviral construct, containing pdx-1 gene, to transfect stem cells towards gene therapy of type-1 diabetes. Methods: In this experimental study, first, the pdx-1 gene was multiplied by PCR from pcDNA3.1-pdx-1 and cloned into pTG19-T vector. Then, pdx-1 was subcloned on upstream of IRES-EGFP gene into IRES2-EGFP vector. At the next step, the cloned parts of IRES-EGFP and pdx-1 were isolated and cloned into the lentiviral expression vector pSINTREM in upstream of TRE-CMV gene. After sequencing, final construct was transfected into HEK 293 cells and gene expression of pdx-1 was evaluated using flow cytometry analysis and reverse fluorescent microscopy. Results: Flow cytometry results and inverted fluorescent microscopy observing showed that pdx-1 and GFP genes are expressed in cells transfected with final recombinant construct. Conclusion: Regarding the design of this construct, to ensure long time expression with higher in vivo and in vitro expression efficiency for stem cells and also use of Tet on induced optimized system, it seems that the current construct can be among the best ones to transfect stem cells. Key words: Gene therapy, Diabetes, Stem cells

The gene therapy revolution in ophthalmology.

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Al-Saikhan, Fahad I

2013-04-01

The advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber's Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa. By using dog models, researchers have made progress in studying X-linked retinitis pigmentosa which results from a RPGR gene mutation. Mouse and canine models have also been used in the study of LCA. The widely studied form of LCA is LCA2, resulting from a mutation in the gene RPE65. Mice and canines that were injected with normal copies of RPE65 gene showed signs such as improved retinal pigment epithelium transduction, visual acuity, and functional recovery. Studies on Stargardt disease have shown that mutations in the ABCA4 gene can be corrected with AAV vectors, or nanoparticles. Gene therapy for the treatment of red-green color blindness was successful in squirrel monkeys. Plans are at an advanced stage to begin clinical trials. Researchers have also proved that CD59 can be used with AMD. Gene therapy is also able to treat primary open angle glaucoma (POAG) in animal models, and studies show it is economically viable.

Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

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Atkinson Mark A

2011-02-01

Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

Nanoparticles for cancer gene therapy: Recent advances, challenges, and strategies.

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Wang, Kui; Kievit, Forrest M; Zhang, Miqin

2016-12-01

Compared to conventional treatments, gene therapy offers a variety of advantages for cancer treatment including high potency and specificity, low off-target toxicity, and delivery of multiple genes that concurrently target cancer tumorigenesis, recurrence, and drug resistance. In the past decades, gene therapy has undergone remarkable progress, and is now poised to become a first line therapy for cancer. Among various gene delivery systems, nanoparticles have attracted much attention because of their desirable characteristics including low toxicity profiles, well-controlled and high gene delivery efficiency, and multi-functionalities. This review provides an overview on gene therapeutics and gene delivery technologies, and highlight recent advances, challenges and insights into the design and the utility of nanoparticles in gene therapy for cancer treatment. Copyright © 2016. Published by Elsevier Ltd.

Nonviral Delivery Systems For Cancer Gene Therapy: Strategies And Challenges.

Science.gov (United States)

Shim, Gayong; Kim, Dongyoon; Le, Quoc-Viet; Park, Gyu Thae; Kwon, Taekhyun; Oh, Yu-Kyoung

2018-01-19

Gene therapy has been receiving widespread attention due to its unique advantage in regulating the expression of specific target genes. In the field of cancer gene therapy, modulation of gene expression has been shown to decrease oncogenic factors in cancer cells or increase immune responses against cancer. Due to the macromolecular size and highly negative physicochemical features of plasmid DNA, efficient delivery systems are an essential ingredient for successful gene therapy. To date, a variety of nanostructures and materials have been studied as nonviral gene delivery systems. In this review, we will cover nonviral delivery strategies for cancer gene therapy, with a focus on target cancer genes and delivery materials. Moreover, we will address current challenges and perspectives for nonviral delivery-based cancer gene therapeutics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A Safeguard System for Induced Pluripotent Stem Cell-Derived Rejuvenated T Cell Therapy

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Miki Ando

2015-10-01

Full Text Available The discovery of induced pluripotent stem cells (iPSCs has created promising new avenues for therapies in regenerative medicine. However, the tumorigenic potential of undifferentiated iPSCs is a major safety concern for clinical translation. To address this issue, we demonstrated the efficacy of suicide gene therapy by introducing inducible caspase-9 (iC9 into iPSCs. Activation of iC9 with a specific chemical inducer of dimerization (CID initiates a caspase cascade that eliminates iPSCs and tumors originated from iPSCs. We introduced this iC9/CID safeguard system into a previously reported iPSC-derived, rejuvenated cytotoxic T lymphocyte (rejCTL therapy model and confirmed that we can generate rejCTLs from iPSCs expressing high levels of iC9 without disturbing antigen-specific killing activity. iC9-expressing rejCTLs exert antitumor effects in vivo. The system efficiently and safely induces apoptosis in these rejCTLs. These results unite to suggest that the iC9/CID safeguard system is a promising tool for future iPSC-mediated approaches to clinical therapy.

Interferon induced IFIT family genes in host antiviral defense.

Science.gov (United States)

Zhou, Xiang; Michal, Jennifer J; Zhang, Lifan; Ding, Bo; Lunney, Joan K; Liu, Bang; Jiang, Zhihua

2013-01-01

Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity and in fact, IFNs exert their antiviral activities through the induction of antiviral proteins. The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among hundreds of IFN-stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5; however, bird, marsupial, frog and fish have only IFIT5. Regardless of species, IFIT5 is always adjacent to SLC16A12. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. However, some viruses can escape the antiviral functions of the IFIT family by suppressing IFIT family genes expression or methylation of 5' cap of viral molecules. In addition, the variants of IFIT family genes could significantly influence the outcome of hepatitis C virus (HCV) therapy. We believe that our current review provides a comprehensive picture for the community to understand the structure and function of IFIT family genes in response to pathogens in human, as well as in animals.

Cystic Fibrosis Gene Therapy in the UK and Elsewhere

Science.gov (United States)

Pytel, Kamila M.; Alton, Eric W.F.W.

2015-01-01

Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) gene was identified in 1989. This opened the door for the development of cystic fibrosis (CF) gene therapy, which has been actively pursued for the last 20 years. Although 26 clinical trials involving approximately 450 patients have been carried out, the vast majority of these trials were short and included small numbers of patients; they were not designed to assess clinical benefit, but to establish safety and proof-of-concept for gene transfer using molecular end points such as the detection of recombinant mRNA or correction of the ion transport defect. The only currently published trial designed and powered to assess clinical efficacy (defined as improvement in lung function) administered AAV2-CFTR to the lungs of patients with CF. The U.K. Cystic Fibrosis Gene Therapy Consortium completed, in the autumn of 2014, the first nonviral gene therapy trial designed to answer whether repeated nonviral gene transfer (12 doses over 12 months) can lead to clinical benefit. The demonstration that the molecular defect in CFTR can be corrected with small-molecule drugs, and the success of gene therapy in other monogenic diseases, is boosting interest in CF gene therapy. Developments are discussed here. PMID:25838137

Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells.

Science.gov (United States)

Li, Yao; Chan, Lawrence; Nguyen, Huy V; Tsang, Stephen H

2016-01-01

Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.

Prevailing public perceptions of the ethics of gene therapy.

Science.gov (United States)

Robillard, Julie M; Roskams-Edris, Dylan; Kuzeljevic, Boris; Illes, Judy

2014-08-01

Gene therapy research is advancing rapidly, and hopes of treating a large number of brain disorders exist alongside ethical concerns. Most surveys of public attitudes toward these ethical issues are already dated and the content of these surveys has been researcher-driven. To examine current public perceptions, we developed an online instrument that is responsive and relevant to the latest research about ethics, gene therapy, and the brain. The 16-question survey was launched with the platform Amazon Mechanical Turk and was made available to residents of Canada and the United States. The survey was divided into six themes: (1) demographic information, (2) general opinions about gene therapy, (3) medical applications of gene therapy, (4) identity and moral/belief systems, (5) enhancement, and (6) risks. We received and analyzed responses from a total of 467 participants. Our results show that a majority of respondents (>90%) accept gene therapy as a treatment for severe illnesses such as Alzheimer disease, but this receptivity decreases for conditions perceived as less severe such as attention deficit hyperactivity disorder (79%), and for nontherapeutic applications (47%). The greatest area of concern for the application of gene therapy to brain conditions is the fear of not receiving sufficient information before undergoing the treatment. The main ethical concerns with enhancement were the potential for disparities in resource allocation, access to the procedure, and discrimination. When comparing these data with those from the 1990s, our findings suggest that the acceptability of gene therapy is increasing and that this trend is occurring despite lingering concerns over ethical issues. Providing the public and patients with up-to-date information and opportunities to engage in the discourse about areas of research in gene therapy is a priority.

Myostatin propeptide gene delivery by gene gun ameliorates muscle atrophy in a rat model of botulinum toxin-induced nerve denervation.

Science.gov (United States)

Tsai, Sen-Wei; Tung, Yu-Tang; Chen, Hsiao-Ling; Yang, Shang-Hsun; Liu, Chia-Yi; Lu, Michelle; Pai, Hui-Jing; Lin, Chi-Chen; Chen, Chuan-Mu

2016-02-01

Muscle atrophy is a common symptom after nerve denervation. Myostatin propeptide, a precursor of myostatin, has been documented to improve muscle growth. However, the mechanism underlying the muscle atrophy attenuation effects of myostatin propeptide in muscles and the changes in gene expression are not well established. We investigated the possible underlying mechanisms associated with myostatin propeptide gene delivery by gene gun in a rat denervation muscle atrophy model, and evaluated gene expression patterns. In a rat botulinum toxin-induced nerve denervation muscle atrophy model, we evaluated the effects of wild-type (MSPP) and mutant-type (MSPPD75A) of myostatin propeptide gene delivery, and observed changes in gene activation associated with the neuromuscular junction, muscle and nerve. Muscle mass and muscle fiber size was moderately increased in myostatin propeptide treated muscles (pmyostatin propeptide gene delivery, especially the mutant-type of MSPPD75A, attenuates muscle atrophy through myogenic regulatory factors and acetylcholine receptor regulation. Our data concluded that myostatin propeptide gene therapy may be a promising treatment for nerve denervation induced muscle atrophy. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene therapy for CNS diseases – Krabbe disease

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Mohammad A. Rafi

2016-06-01

Full Text Available This is a brief report of the 19th Annual Meeting of the American Society of Gene and Cell Therapy that took place from May 4th through May 7th, 2016 in Washington, DC, USA. While the meeting provided many symposiums, lectures, and scientific sessions this report mainly focuses on one of the sessions on the "Gene Therapy for central nervous system (CNS Diseases" and specifically on the "Gene Therapy for the globoid cell leukodystrophy or Krabbe disease. Two presentations focused on this subject utilizing two animal models of this disease: mice and dog models. Different serotypes of adeno-associate viral vectors (AAV alone or in combination with bone marrow transplantations were used in these research projects. The Meeting of the ASGCT reflected continuous growth in the fields of gene and cell therapy and brighter forecast for efficient treatment options for variety of human diseases.

Analysis of the clonal repertoire of gene-corrected cells in gene therapy.

Science.gov (United States)

Paruzynski, Anna; Glimm, Hanno; Schmidt, Manfred; Kalle, Christof von

2012-01-01

Gene therapy-based clinical phase I/II studies using integrating retroviral vectors could successfully treat different monogenetic inherited diseases. However, with increased efficiency of this therapy, severe side effects occurred in various gene therapy trials. In all cases, integration of the vector close to or within a proto-oncogene contributed substantially to the development of the malignancies. Thus, the in-depth analysis of integration site patterns is of high importance to uncover potential clonal outgrowth and to assess the safety of gene transfer vectors and gene therapy protocols. The standard and nonrestrictive linear amplification-mediated PCR (nrLAM-PCR) in combination with high-throughput sequencing exhibits technologies that allow to comprehensively analyze the clonal repertoire of gene-corrected cells and to assess the safety of the used vector system at an early stage on the molecular level. It enables clarifying the biological consequences of the vector system on the fate of the transduced cell. Furthermore, the downstream performance of real-time PCR allows a quantitative estimation of the clonality of individual cells and their clonal progeny. Here, we present a guideline that should allow researchers to perform comprehensive integration site analysis in preclinical and clinical studies. Copyright © 2012 Elsevier Inc. All rights reserved.

Gene therapy for cartilage and bone tissue engineering

CERN Document Server

Hu, Yu-Chen

2014-01-01

"Gene Therapy for Cartilage and Bone Tissue Engineering" outlines the tissue engineering and possible applications of gene therapy in the field of biomedical engineering as well as basic principles of gene therapy, vectors and gene delivery, specifically for cartilage and bone engineering. It is intended for tissue engineers, cell therapists, regenerative medicine scientists and engineers, gene therapist and virologists. Dr. Yu-Chen Hu is a Distinguished Professor at the Department of Chemical Engineering, National Tsing Hua University and has received the Outstanding Research Award (National Science Council), Asia Research Award (Society of Chemical Engineers, Japan) and Professor Tsai-Teh Lai Award (Taiwan Institute of Chemical Engineers). He is also a fellow of the American Institute for Medical and Biological Engineering (AIMBE) and a member of the Tissue Engineering International & Regenerative Medicine Society (TERMIS)-Asia Pacific Council.

Gene therapy for the inner ear: challenges and promises.

Science.gov (United States)

Ryan, Allen F; Dazert, Stefan

2009-01-01

Since the recognition of genes as the discrete units of heritability, and of DNA as their molecular substrate, the utilization of genes for therapeutic purposes has been recognized as a potential means of correcting genetic disorders. The tools of molecular biology, which allow the manipulation of DNA sequence, provided the means to put this concept into practice. However, progress in the implementation of these ideas has been slow. Here we review the history of the idea of gene therapy and the complexity of genetic disorders. We also discuss the requirements for sequence-based therapy to be accomplished for different types of inherited diseases, as well as the methods available for gene manipulation. The challenges that have limited the applications of gene therapy are reviewed, as are ethical concerns. Finally, we discuss the promise of gene therapy to address inherited and acquired disorders of the inner ear. Copyright (c) 2009 S. Karger AG, Basel.

High Intensity Focused Ultrasound for Cancer Therapy--harnessing its non-linearity

International Nuclear Information System (INIS)

Haar, Gail ter

2008-01-01

In medicine in general, and for cancer treatments in particular, there is a drive to find effective non-invasive therapies. High Intensity Focused Ultrasound (HIFU) represents one such technique. In principle, it is simple--a high energy ultrasound beam is brought to a tight focus within a target which may lie several centimetres below the skin surface (for example, in a tumour of the liver), and is used to destroy a selected tissue volume. The main mechanism for cell killing in a HIFU beam is heat. Ultrasound energy absorption is frequency dependent, the higher frequencies being absorbed most strongly. Significant thermal advantage may therefore be gained from non-linear propagation, which generates higher harmonics, in tissue. Acoustic cavitation and thermal exsolution of gas (boiling) also contribute to tissue damage. This activity leads to the local mechanical disruption of cells. In addition, the non-linear oscillation of these bubbles leads to enhanced energy deposition. The acoustic emissions from such bubbles are characteristic of their behaviour and may be correlated to some extent with the appearance of the disruption produced. The more widespread clinical acceptance of HIFU is awaiting faster, and more efficient, energy delivery and treatment monitoring. A better understanding of the nonlinear aspects of HIFU propagation in tissue is thus important if this technique is to benefit more patients

Effect of high-intensity focused ultrasound (HIFU combined with radiotherapy on tumor malignancy in patients with advanced pancreatic cancer and evaluation of side effects

Directory of Open Access Journals (Sweden)

Jing Li

2017-02-01

Full Text Available Objective: To study the effect of high-intensity focused ultrasound (HIFU combined with radiotherapy on tumor malignancy in patients with advanced pancreatic cancer and the corresponding side effects. Methods: A total of 84 patients with advanced pancreatic cancer treated in our hospital between May 2013 and March 2016 were selected and randomly divided into HIFU group and IGRT group, HIFU group accepted high-intensity focused ultrasound combined with radiotherapy and IGRT group received radiotherapy alone. 4 weeks after treatment, the levels of tumor markers, liver and kidney function indexes, perineural invasionrelated molecules and cytokines in serum as well as the levels of immune cells in peripheral blood were determined. Results: 4 weeks after treatment, serum CA199, CA242, OPN, NGAL, RBP4, NGF, TrkA, p75, BDNF and TrkB levels of HIFU group were significantly lower than those of IGRT group, serum IL-2, TNF-毩, IFN-γ and IL-13 levels as well as peripheral blood NKT cell and CD4+T cell levels were significantly higher than those of IGRT group, and serum ALT, AST, Cr and BUN levels were not significantly different from those of IGRT group. Conclusion: HIFU combined with radiotherapy treatment of advanced pancreatic cancer can more effectively kill cancer cells, inhibit pancreatic cancer cell invasion to the peripheral nerve and enhance the antitumor immune response mediated by NKT cells and CD4+T cells.

Current status of gene therapy for motor neuron disease

Institute of Scientific and Technical Information of China (English)

Xingkai An; Rong Peng; Shanshan Zhao

2006-01-01

OBJECTIVE: Although the etiology and pathogenesis of motor neuron disease is still unknown, there are many hypotheses on motor neuron mitochondrion, cytoskeleton structure and functional injuries. Thus, gene therapy of motor neuron disease has become a hot topic to apply in viral vector, gene delivery and basic gene techniques.DATA SOURCES: The related articles published between January 2000 and October 2006 were searched in Medline database and ISl database by computer using the keywords "motor neuron disease, gene therapy", and the language is limited to English. Meanwhile, the related references of review were also searched by handiwork. STUDY SELECTION: Original articles and referred articles in review were chosen after first hearing, then the full text which had new ideas were found, and when refer to the similar study in the recent years were considered first.DATA EXTRACTION: Among the 92 related articles, 40 ones were accepted, and 52 were excluded because of repetitive study or reviews.DATA SYNTHESIS: The viral vectors of gene therapy for motor neuron disease include adenoviral, adeno-associated viral vectors, herpes simplex virus type 1 vectors and lentiviral vectors. The delivery of them can be achieved by direct injection into the brain, or by remote delivery after injection vectors into muscle or peripheral nerves, or by ex vivo gene transfer. The viral vectors of gene therapy for motor neuron disease have been successfully developed, but the gene delivery of them is hampered by some difficulties. The RNA interference and neuroprotection are the main technologies for gene-based therapy in motor neuron disease. CONCLUSION : The RNA interference for motor neuron disease has succeeded in animal models, and the neuroprotection also does. But, there are still a lot of questions for gene therapy in the clinical treatment of motor neuron disease.

Gene therapy imaging in patients for oncological applications

International Nuclear Information System (INIS)

Penuelas, Ivan; Haberkorn, Uwe; Yaghoubi, Shahriar; Gambhir, Sanjiv S.

2005-01-01

Thus far, traditional methods for evaluating gene transfer and expression have been shown to be of limited value in the clinical arena. Consequently there is a real need to develop new methods that could be repeatedly and safely performed in patients for such purposes. Molecular imaging techniques for gene expression monitoring have been developed and successfully used in animal models, but their sensitivity and reproducibility need to be tested and validated in human studies. In this review, we present the current status of gene therapy-based anticancer strategies and show how molecular imaging, and more specifically radionuclide-based approaches, can be used in gene therapy procedures for oncological applications in humans. The basis of gene expression imaging is described and specific uses of these non-invasive procedures for gene therapy monitoring illustrated. Molecular imaging of transgene expression in humans and evaluation of response to gene-based therapeutic procedures are considered. The advantages of molecular imaging for whole-body monitoring of transgene expression as a way to permit measurement of important parameters in both target and non-target organs are also analyzed. The relevance of this technology for evaluation of the necessary vector dose and how it can be used to improve vector design are also examined. Finally, the advantages of designing a gene therapy-based clinical trial with imaging fully integrated from the very beginning are discussed and future perspectives for the development of these applications outlined. (orig.)

Gene Therapy: Potential, Pros, Cons and Ethics

OpenAIRE

Ananth Nanjunda Rao

2002-01-01

Genetic technology poses risks along with its rewards, just as any technology has in the past. To stop its development and forfeit the benefits gene therapy could offer would be a far greater mistake than forging ahead could ever be. People must always try to be responsible with their new technology, but gene therapy has the potential to be the future of medicine and its possibilities must be explored.

Communicating the promise for ocular gene therapies: challenges and recommendations.

Science.gov (United States)

Benjaminy, Shelly; Kowal, Stephanie P; MacDonald, Ian M; Bubela, Tania

2015-09-01

To identify challenges and pose solutions for communications about ocular gene therapy between patients and clinicians as clinical research progresses. Literature review with recommendations. Literature review of science communication best practices to inform recommendations for patient-clinician discussions about ocular gene therapy. Clinicians need to employ communications about ocular gene therapy that are both attentive to patient priorities and concerns and responsive to other sources of information, including overly positive news media and the Internet. Coverage often conflates research with therapy-clinical trials are experimental and are not risk free. If proven safe and efficacious, gene therapy may present a treatment but not a cure for patients who have already experienced vision loss. Clinicians can assist patients by providing realistic estimates for lengthy clinical development timelines and positioning current research within models of clinical translation. This enables patients to weigh future therapeutic options when making current disease management decisions. Ocular gene therapy clinical trials are raising hopes for treating a myriad of hereditary retinopathies, but most such therapies are many years in the future. Clinicians should be prepared to counter overly positive messaging, found in news media and on the Internet, with optimism tempered by evidence to support the ethical translation of gene therapy and other novel biotherapeutics. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Enhanced therapeutic effect of multiple injections of HSV-TK + GCV gene therapy in combination with ionizing radiation in a mouse mammary tumor model

International Nuclear Information System (INIS)

Vlachaki, Maria T.; Chhikara, Madhu; Aguilar, Laura; Zhu Xiaohong; Chiu, Kam J.; Woo, Shiao; Teh, Bin S.; Thompson, Timothy C.; Butler, E. Brian; Aguilar-Cordova, Estuardo

2001-01-01

Purpose: Standard therapies for breast cancer lack tumor specificity and have significant risk for recurrence and toxicities. Herpes simplex virus-thymidine kinase (HSV-tk) gene therapy combined with radiation therapy (XRT) may be effective because of complementary mechanisms and distinct toxicity profiles. HSV-tk gene therapy followed by systemic administration of ganciclovir (GCV) enhances radiation-induced DNA damage by generating high local concentrations of phosphorylated nucleotide analogs that increase radiation-induced DNA breaks and interfere with DNA repair mechanisms. In addition, radiation-induced membrane damage enhances the 'bystander effect' by facilitating transfer of nucleotide analogs to neighboring nontransduced cells and by promoting local and systemic immune responses. This study assesses the effect of single and multiple courses of HSV-tk gene therapy in combination with ionizing radiation in a mouse mammary cancer model. Methods and Materials: Mouse mammary TM40D tumors transplanted s.c. in syngeneic immunocompetent BALB-c mice were treated with either adenoviral-mediated HSV-tk gene therapy or local radiation or the combination of gene and radiation therapy. A vector consisting of a replication-deficient (E1-deleted) adenovirus type 5 was injected intratumorally to administer the HSV-tk gene, and GCV was initiated 24 h later for a total of 6 days. Radiation was given as a single dose of 5 Gy 48 h after the HSV-tk injection. A metastatic model was developed by tail vein injection of TM40D cells on the same day that the s.c. tumors were established. Systemic antitumor effect was evaluated by counting the number of lung nodules after treating only the primary tumors with gene therapy, radiation, or the combination of gene and radiation therapy. To assess the therapeutic efficacy of multiple courses of this combinatorial approach, one, two, and three courses of HSV-tk + GCV gene therapy, in combination with radiation, were compared to HSV-tk or

Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction.

Science.gov (United States)

Keswani, Sundeep G; Balaji, Swathi; Katz, Anna B; King, Alice; Omar, Khaled; Habli, Mounira; Klanke, Charles; Crombleholme, Timothy M

2015-03-01

Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal-fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta-specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical translation of

Satellite DNA-based artificial chromosomes for use in gene therapy.

Science.gov (United States)

Hadlaczky, G

2001-04-01

Satellite DNA-based artificial chromosomes (SATACs) can be made by induced de novo chromosome formation in cells of different mammalian species. These artificially generated accessory chromosomes are composed of predictable DNA sequences and they contain defined genetic information. Prototype human SATACs have been successfully constructed in different cell types from 'neutral' endogenous DNA sequences from the short arm of the human chromosome 15. SATACs have already passed a number of hurdles crucial to their further development as gene therapy vectors, including: large-scale purification; transfer of purified artificial chromosomes into different cells and embryos; generation of transgenic animals and germline transmission with purified SATACs; and the tissue-specific expression of a therapeutic gene from an artificial chromosome in the milk of transgenic animals.

Procedural sedation and analgesia for respiratory-gated MR-HIFU in the liver : a feasibility study

NARCIS (Netherlands)

van Breugel, Marjolein; Wijlemans, JW; Vaessen, Hermanus H B; de Greef, Martijn; Moonen, Chrit T W; van den Bosch, Maurice A A J; Ries, Mario G

2016-01-01

BACKGROUND: Previous studies demonstrated both pre-clinically and clinically the feasibility of magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablations in the liver. To overcome the associated problem of respiratory motion of the ablation area, general anesthesia (GA) and

Theranostic GO-based nanohybrid for tumor induced imaging and potential combinational tumor therapy.

Science.gov (United States)

Qin, Si-Yong; Feng, Jun; Rong, Lei; Jia, Hui-Zhen; Chen, Si; Liu, Xiang-Ji; Luo, Guo-Feng; Zhuo, Ren-Xi; Zhang, Xian-Zheng

2014-02-12

Graphene oxide (GO)-based theranostic nanohybrid is designed for tumor induced imaging and potential combinational tumor therapy. The anti-tumor drug, Doxorubicin (DOX) is chemically conjugated to the poly(ethylenimine)-co-poly(ethylene glycol) (PEI-PEG) grafted GO via a MMP2-cleavable PLGLAG peptide linkage. The therapeutic efficacy of DOX is chemically locked and its intrinsic fluorescence is quenched by GO under normal physiological condition. Once stimulated by the MMP2 enzyme over-expressed in tumor tissues, the resulting peptide cleavage permits the unloading of DOX for tumor therapy and concurrent fluorescence recovery of DOX for in situ tumor cell imaging. Attractively, this PEI-bearing nanohybrid can mediate efficient DNA transfection and shows great potential for combinational drug/gene therapy. This tumor induced imaging and potential combinational therapy will open a window for tumor treatment by offering a unique theranostic approach through merging the diagnostic capability and pathology-responsive therapeutic function. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gene Therapy: Potential, Pros, Cons and Ethics

Directory of Open Access Journals (Sweden)

Ananth Nanjunda Rao

2002-07-01

Full Text Available Genetic technology poses risks along with its rewards, just as any technology has in the past. To stop its development and forfeit the benefits gene therapy could offer would be a far greater mistake than forging ahead could ever be. People must always try to be responsible with their new technology, but gene therapy has the potential to be the future of medicine and its possibilities must be explored.

The Pathway From Genes to Gene Therapy in Glaucoma: A Review of Possibilities for Using Genes as Glaucoma Drugs.

Science.gov (United States)

Borrás, Teresa

2017-01-01

Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of re-placing the mutated gene causing the disease to the use of genes to con-trol nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular bi-ology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judg-ing by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration. Copyright© 2017 Asia-Pacific Academy of Ophthalmology.

A History of the Sonocare CST-100: The First FDA-approved HIFU Device

Science.gov (United States)

Muratore, Robert

2006-05-01

The Sonocare CST-100 Therapeutic Ultrasound System, designed for the treatment of glaucoma, was developed in the 1980s and became the first high intensity focused ultrasound (HIFU) device to receive Food and Drug Administration approval. The system arose from studies done by F.L. Lizzi, Eng.Sc.D., of Riverside Research Institute and D.J. Coleman, M.D., of Cornell Medical Center/New York Hospital on the safety of ultrasound diagnosis of the eye. As safety limits were probed, therapeutic regimes were discovered. Optimization of operational parameters, clinical experience, and engineering design came together through a spin-off company, Sonocare, Inc., formed to produce and market the ophthalmic device. Various precedents were set during the approval process, including the acceptance by the FDA of radiation momentum imparted to an absorber as a measure of acoustic power. Many devices were sold, but the laser industry, grandfathered into the therapeutic field, eventually out-marketed Sonocare. The CST-100 remains as a model of elegant industrial design, and existing units are used daily in HIFU laboratory experiments.

Nonviral Technologies for Gene Therapy in Cardiovascular Research

Directory of Open Access Journals (Sweden)

Cheng-Huang Su

2008-06-01

Full Text Available Gene therapy, which is still at an experimental stage, is a technique that attempts to correct or prevent a disease by delivering genes into an individual's cells and tissues. In gene delivery, a vector is a vehicle for transferring genetic material into cells and tissues. Synthetic vectors are considered to be prerequisites for gene delivery, because viral vectors have fundamental problems in relation to safety issues as well as large-scale production. Among the physical approaches, ultrasound with its associated bioeffects such as acoustic cavitation, especially inertial cavitation, can increase the permeability of cell membranes to macromolecules such as plasmid DNA. Microbubbles or ultrasound contrast agents lower the threshold for cavitation by ultrasound energy. Furthermore, ultrasound-enhanced gene delivery using polymers or other nonviral vectors may hold much promise for the future but is currently at the preclinical stage. We all know aging is cruel and inevitable. Currently, among the promising areas for gene therapy in acquired diseases, the incidences of cancer and ischemic cardiovascular diseases are strongly correlated with the aging process. As a result, gene therapy technology may play important roles in these diseases in the future. This brief review focuses on understanding the barriers to gene transfer as well as describing the useful nonviral vectors or tools that are applied to gene delivery and introducing feasible models in terms of ultrasound-based gene delivery.

The use of molecular imaging of gene expression by radiotracers in gene therapy

International Nuclear Information System (INIS)

Richard-Fiardo, P.; Franken, P.R.; Harrington, K.J.; Vassaux, G.; Cambien, B.

2011-01-01

Introduction: Progress with gene-based therapies has been hampered by difficulties in monitoring the biodistribution and kinetics of vector-mediated gene expression. Recent developments in non-invasive imaging have allowed researchers and clinicians to assess the location, magnitude and persistence of gene expression in animals and humans. Such advances should eventually lead to improvement in the efficacy and safety of current clinical protocols for future treatments. Areas Covered: The molecular imaging techniques for monitoring gene therapy in the living subject, with a specific highlight on the key reporter gene approaches that have been developed and validated in preclinical models using the latest imaging modalities. The applications of molecular imaging to biotherapy, with a particular emphasis on monitoring of gene and vector biodistribution and on image-guided radiotherapy. Expert Opinion: Among the reporter gene/probe combinations that have been described so far, one stands out, in our view, as the most versatile and easy to implement: the Na/I symporter. This strategy, exploiting more than 50 years of experience in the treatment of differentiated thyroid carcinomas, has been validated in different types of experimental cancers and with different types of oncolytic viruses and is likely to become a key tool in the implementation of human gene therapy. (authors)

The molecular mechanism of gene-radiotherapy of tumor

International Nuclear Information System (INIS)

Zhu Xian

2004-01-01

Gene-radiotherapy of tumor is a new method which is induced by ionizing radiation. The molecular mechanism is to activate various molecular target by many ways and induce the apoptosis of tumor cell. It is a gene therapy based on the radiation-inducible property of the Egr-1 gene. It has good application prospect in therapy of tumor

Soluble TGF-β type II receptor gene therapy reduces TGF-β activity in irradiated lung tissue and protects lungs from radiation-induced injury

International Nuclear Information System (INIS)

Vujaskovic, Z.; Rabbani, Z.; Zhang, X.; Samulski, T.V.; Li, C.-Y.; Anscher, M.S.

2003-01-01

Full text: The objective was to determine whether administration of recombinant human adenoviral vector carrying soluble TGF-β1 type II receptor (TβR-II) gene reduces availability of active TGFβ1 and protects lung from radiation-induced injury. Female Fisher-344 rats were randomized into four groups to receive: 1) Control 2) Adenoviral green fluorescent protein vector (AdGFP) alone 3) Radiation (RT) + Adenoviral vector with TGF-β1 type II receptor gene (AdexTβR-II-Fc) 4) RT alone. Animals were irradiated to right hemithorax using a single dose of 30 Gy. The packaging and production of a recombinant adenovirus carrying the fused human TβR-II-IgG1 Fc gene was achieved by use of the AdEasy system. The treatment vector AdexTbR-II-Fc (1.5*1010 PFU) and control vector AdGFP (1*109 PFU) were injected i.v. 24 hrs after RT. Respiratory rate was measured as an index of pulmonary function weekly for 5 weeks post RT. Structural damage was scored histologically. Immunohistochemistry was performed to identify activated macrophages. ELISA was used to quantify active TGF-β1 in tissue homogenate. Western blot was used to determine TβR-II expression in plasma and lung tissue. Animals receiving treatment vector AdexTbR-II-Fc have elevated plasma levels of soluble TβR-II at 24 and 48 hours after injection. In the RT+AdexTbR-II-Fc group, there was a significant reduction in respiratory rate (p = 0.002) at four weeks after treatment compared to RT alone group. Histology revealed a significant reduction in lung structural damage in animals receiving gene therapy after RT vs RT alone (p=0.0013). There was also a decrease in the number of activated macrophage (p= 0.02) in RT+AdexTbR-II-Fc group vs RT alone. The tissue protein expression of active TGF-β1 was significantly reduced in rats receiving RT+AdexTbR-II-Fc treatment (p<0.05). This study shows the ability of adenovirus mediated soluble TβR-II gene therapy to reduce tissue levels of active TGF-β1 and ameliorate radiation-induced

Nerve Growth Factor Gene Therapy Activates Neuronal Responses in Alzheimer’s Disease

Science.gov (United States)

Tuszynski, Mark H.; Yang, Jennifer H.; Barba, David; U, H S.; Bakay, Roy; Pay, Mary M.; Masliah, Eliezer; Conner, James M.; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H.

2016-01-01

IMPORTANCE Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and lacks effective disease modifying therapies. In 2001 we initiated a clinical trial of Nerve Growth Factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in AD patients. We present post-mortem findings in 10 subjects with survival times ranging from 1 to 10 years post-treatment. OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS 10 patients with early AD underwent NGF gene therapy using either ex vivo or in vivo gene transfer. The brains of all eight patients in the first Phase 1 ex vivo trial and two patients in a subsequent Phase 1 in vivo trial were examined. MAIN OUTCOME MEASURES Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In two cases, NGF protein levels were measured by ELISA. RESULTS Degenerating neurons in the AD brain respond to NGF. All patients exhibited a trophic response to NGF, in the form of axonal sprouting toward the NGF source. Comparing treated and non-treated sides of the brain in three patients that underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P>0.05). Activation of cellular signaling and functional markers were present in two patients that underwent AAV2-mediated NGF gene transfer. Neurons exhibiting tau pathology as well as neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes with resulting activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE These findings indicate that

Positron emission tomography and gene therapy: basic concepts and experimental approaches for in vivo gene expression imaging.

Science.gov (United States)

Peñuelas, Iván; Boán, JoséF; Martí-Climent, Josep M; Sangro, Bruno; Mazzolini, Guillermo; Prieto, Jesús; Richter, José A

2004-01-01

More than two decades of intense research have allowed gene therapy to move from the laboratory to the clinical setting, where its use for the treatment of human pathologies has been considerably increased in the last years. However, many crucial questions remain to be solved in this challenging field. In vivo imaging with positron emission tomography (PET) by combination of the appropriate PET reporter gene and PET reporter probe could provide invaluable qualitative and quantitative information to answer multiple unsolved questions about gene therapy. PET imaging could be used to define parameters not available by other techniques that are of substantial interest not only for the proper understanding of the gene therapy process, but also for its future development and clinical application in humans. This review focuses on the molecular biology basis of gene therapy and molecular imaging, describing the fundamentals of in vivo gene expression imaging by PET, and the application of PET to gene therapy, as a technology that can be used in many different ways. It could be applied to avoid invasive procedures for gene therapy monitoring; accurately diagnose the pathology for better planning of the most adequate therapeutic approach; as treatment evaluation to image the functional effects of gene therapy at the biochemical level; as a quantitative noninvasive way to monitor the location, magnitude and persistence of gene expression over time; and would also help to a better understanding of vector biology and pharmacology devoted to the development of safer and more efficient vectors.

CRISPR-Cas9: a promising tool for gene editing on induced pluripotent stem cells.

Science.gov (United States)

Kim, Eun Ji; Kang, Ki Ho; Ju, Ji Hyeon

2017-01-01

Recent advances in genome editing with programmable nucleases have opened up new avenues for multiple applications, from basic research to clinical therapy. The ease of use of the technology-and particularly clustered regularly interspaced short palindromic repeats (CRISPR)-will allow us to improve our understanding of genomic variation in disease processes via cellular and animal models. Here, we highlight the progress made in correcting gene mutations in monogenic hereditary disorders and discuss various CRISPR-associated applications, such as cancer research, synthetic biology, and gene therapy using induced pluripotent stem cells. The challenges, ethical issues, and future prospects of CRISPR-based systems for human research are also discussed.

CRISPR-Cas9: a promising tool for gene editing on induced pluripotent stem cells

Science.gov (United States)

Kim, Eun Ji; Kang, Ki Ho; Ju, Ji Hyeon

2017-01-01

Recent advances in genome editing with programmable nucleases have opened up new avenues for multiple applications, from basic research to clinical therapy. The ease of use of the technology—and particularly clustered regularly interspaced short palindromic repeats (CRISPR)—will allow us to improve our understanding of genomic variation in disease processes via cellular and animal models. Here, we highlight the progress made in correcting gene mutations in monogenic hereditary disorders and discuss various CRISPR-associated applications, such as cancer research, synthetic biology, and gene therapy using induced pluripotent stem cells. The challenges, ethical issues, and future prospects of CRISPR-based systems for human research are also discussed. PMID:28049282

Non-invasive high-intensity focused ultrasound for UV-induced hyperpigmentation in Fitzpatrick skin types III and IV: a prospective, randomized, controlled, evaluator-blinded trial.

Science.gov (United States)

Vachiramon, Vasanop; Jurairattanaporn, Natthachat; Harnchoowong, Sarawin; Chayavichitsilp, Pamela

2018-02-01

Skin hyperpigmentation is a frequently encountered problem, particularly in darker skin types. Unfortunately, standard treatments for this condition have shown disappointing results. High-intensity focused ultrasound (HIFU) is commonly indicated for skin laxity, but recently was used to treat UV-induced hyperpigmentation in animal models. This study is aimed to evaluate the efficacy and safety of high-intensity focused ultrasound for UVB-induced hyperpigmentation in human subjects. A randomized, evaluator-blinded pilot study was conducted on 20 subjects. Each subject was induced three hyperpigmentary spots by local broadband UVB. After 2 weeks, each spot was randomly allocated to control, low-energy, and high-energy HIFU. Subjects were instructed to follow up weekly for a duration of 1 month. Lightness index measurements, mean improvement scores, subjects' satisfaction, pain scores, and side effects were evaluated. All 20 subjects completed the study. Fourteen subjects had Fitzpatrick (FPT) skin type III and six subjects had FPT skin type IV. Twelve subjects showed greater improvement at control sites while eight subjects showed greater improvement at HIFU-treated sites. In FPT skin type III, HIFU appeared to be inferior to control in both lightness index and mean improvement scores, but in FPT skin type IV, HIFU had greater lightness index improvement and higher improvement scores than control. Side effects were more frequent in high-energy-treated areas. Focused ultrasound may be offered in some patients with hyperpigmentary conditions. More research is needed to determine proper energy settings for optimal outcome.

Efficacious and safe tissue-selective controlled gene therapy approaches for the cornea.

Directory of Open Access Journals (Sweden)

Rajiv R Mohan

2011-04-01

Full Text Available Untargeted and uncontrolled gene delivery is a major cause of gene therapy failure. This study aimed to define efficient and safe tissue-selective targeted gene therapy approaches for delivering genes into keratocytes of the cornea in vivo using a normal or diseased rabbit model. New Zealand White rabbits, adeno-associated virus serotype 5 (AAV5, and a minimally invasive hair-dryer based vector-delivery technique were used. Fifty microliters of AAV5 titer (6.5×10(12 vg/ml expressing green fluorescent protein gene (GFP was topically applied onto normal or diseased (fibrotic or neovascularized rabbit corneas for 2-minutes with a custom vector-delivery technique. Corneal fibrosis and neovascularization in rabbit eyes were induced with photorefractive keratectomy using excimer laser and VEGF (630 ng using micropocket assay, respectively. Slit-lamp biomicroscopy and immunocytochemistry were used to confirm fibrosis and neovascularization in rabbit corneas. The levels, location and duration of delivered-GFP gene expression in the rabbit stroma were measured with immunocytochemistry and/or western blotting. Slot-blot measured delivered-GFP gene copy number. Confocal microscopy performed in whole-mounts of cornea and thick corneal sections determined geometric and spatial localization of delivered-GFP in three-dimensional arrangement. AAV5 toxicity and safety were evaluated with clinical eye exam, stereomicroscopy, slit-lamp biomicroscopy, and H&E staining. A single 2-minute AAV5 topical application via custom delivery-technique efficiently and selectively transduced keratocytes in the anterior stroma of normal and diseased rabbit corneas as evident from immunocytochemistry and confocal microscopy. Transgene expression was first detected at day 3, peaked at day 7, and was maintained up to 16 weeks (longest tested time point. Clinical and slit-lamp eye examination in live rabbits and H&E staining did not reveal any significant changes between AAV5

Gene therapy in dentistry: tool of genetic engineering. Revisited.

Science.gov (United States)

Gupta, Khushboo; Singh, Saurabh; Garg, Kavita Nitish

2015-03-01

Advances in biotechnology have brought gene therapy to the forefront of medical research. The concept of transferring genes to tissues for clinical applications has been discussed nearly half a century, but the ability to manipulate genetic material via recombinant DNA technology has brought this goal to reality. The feasibility of gene transfer was first demonstrated using tumour viruses. This led to development of viral and nonviral methods for the genetic modification of somatic cells. Applications of gene therapy to dental and oral problems illustrate the potential impact of this technology on dentistry. Preclinical trial results regarding the same have been very promising. In this review we will discuss methods, vectors involved, clinical implication in dentistry and scientific issues associated with gene therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Development of Non-Viral, Trophoblast-Specific Gene Delivery for Placental Therapy.

Directory of Open Access Journals (Sweden)

Noura Abd Ellah

Full Text Available Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1. Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.

Hypoxia-targeted suicidal gene therapy system enhances antitumor effects of radiotherapy

International Nuclear Information System (INIS)

Liu Junye; Guo Yao; Guo Guozhen

2006-01-01

Objective: To explore the effects of hypoxia-targeted suicidal gene therapy system combined with radiotherapy on pancreatic cancer. Methods: The recombinant adenovirus Ad-5HRE/hCMVmp-BCD was constructed by DNA recombinant technique. Western blot was used to detect hypoxia-induced expression of bacterial cytosine deaminase (BCD). Cell growth inhibition assay was used to determine the sensitivity of human pancreatic cancer cells MIA-PACA2 to 5-fluorocytosine (5-FC). Tumor xenograft growth delay assays was used to evaluate the effects of Ad-5HRE/hCMVmp-BCD/5-FC combined with radiotherapy on pancreatic cancer. Results: Western blot analysis demonstrated that hypoxia-induced BCD protein expression was achieved in MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD. With hypoxia treatment, the sensitivity of MIA-PACA2 cells infected with Ad-5HRE/hCMVmp-BCD to 5-FC significantly increased. Administration of either Ad-5HRE/hCMVmp-BCD/5-FC or radiotherapy could inhibit the growth of MIA-PACA2 xenografts in nude mice. Moreover, combination of Ad-5HRE/hCMVmp-BCD/5-FC could significantly enhance suppressing effects of radiotherapy on MIA-PACA2 xenografts. Conclusion: Hypoxia-targeted suicidal gene therapy system Ad-5HRE/hCMVmp-BCD/5-FC could enhance antitumor effects of radiotherapy on pancreatic cancer and can be used as a powerful adjunct to conventional radiotherapy. (authors)

Fast lesion mapping during HIFU treatment using harmonic motion imaging guided focused ultrasound (HMIgFUS) in vitro and in vivo

Science.gov (United States)

Han, Yang; Wang, Shutao; Payen, Thomas; Konofagou, Elisa

2017-04-01

The successful clinical application of high intensity focused ultrasound (HIFU) ablation depends on reliable monitoring of the lesion formation. Harmonic motion imaging guided focused ultrasound (HMIgFUS) is an ultrasound-based elasticity imaging technique, which monitors HIFU ablation based on the stiffness change of the tissue instead of the echo intensity change in conventional B-mode monitoring, rendering it potentially more sensitive to lesion development. Our group has shown that predicting the lesion location based on the radiation force-excited region is feasible during HMIgFUS. In this study, the feasibility of a fast lesion mapping method is explored to directly monitor the lesion map during HIFU. The harmonic motion imaging (HMI) lesion map was generated by subtracting the reference HMI image from the present HMI peak-to-peak displacement map, as streamed on the computer display. The dimensions of the HMIgFUS lesions were compared against gross pathology. Excellent agreement was found between the lesion depth (r 2  =  0.81, slope  =  0.90), width (r 2  =  0.85, slope  =  1.12) and area (r 2  =  0.58, slope  =  0.75). In vivo feasibility was assessed in a mouse with a pancreatic tumor. These findings demonstrate that HMIgFUS can successfully map thermal lesions and monitor lesion development in real time in vitro and in vivo. The HMIgFUS technique may therefore constitute a novel clinical tool for HIFU treatment monitoring.

Gene therapy of cancer and development of therapeutic target gene

Energy Technology Data Exchange (ETDEWEB)

Kim, Chang Min; Kwon, Hee Chung

1998-04-01

We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

Gene therapy of cancer and development of therapeutic target gene

International Nuclear Information System (INIS)

Kim, Chang Min; Kwon, Hee Chung

1998-04-01

We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

Gene expression profiles in cervical cancer with radiation therapy alone and chemo-radiation therapy

International Nuclear Information System (INIS)

Lee, Kyu Chan; Kim, Joo Young; Hwang, You Jin; Kim, Meyoung Kon; Choi, Myung Sun; Kim, Chul Young

2003-01-01

To analyze the gene expression profiles of uterine cervical cancer, and its variation after radiation therapy, with or without concurrent chemotherapy, using a cDNA microarray. Sixteen patients, 8 with squamous cell carcinomas of the uterine cervix, who were treated with radiation alone, and the other 8 treated with concurrent chemo-radiation, were included in the study. Before the starting of the treatment, tumor biopsies were carried out, and the second time biopsies were performed after a radiation dose of 16.2-27 Gy. Three normal cervix tissues were used as a control group. The microarray experiments were performed with 5 groups of the total RNAs extracted individually and then admixed as control, pre-radiation therapy alone, during-radiation therapy alone, pre-chemoradiation therapy, and during chemoradiation therapy. The 33P-labeled cDNAs were synthesized from the total RNAs of each group, by reverse transcription, and then they were hybridized to the cDNA microarray membrane. The gene expression of each microarrays was captured by the intensity of each spot produced by the radioactive isotopes. The pixels per spot were counted with an Arrayguage, and were exported to Microsoft Excel. The data were normalized by the Z transformation, and the comparisons were performed on the Z-ratio values calculated. The expressions of 15 genes, including integrin linked kinase (ILK), CDC28 protein kinase 2, Spry 2, and ERK 3, were increased with the Z-ratio values of over 2.0 for the cervix cancer tissues compared to those for the normal controls. Those genes were involved in cell growth and proliferation, cell cycle control, or signal transduction. The expressions of the other 6 genes, including G protein coupled receptor kinase 6, were decreased with the Z-ratio values of below -2.0. After the radiation therapy, most of the genes, with a previously increase expressions, represented the decreased expression profiles, and the genes, with the Z-ratio values of over 2.0, were

Gene and cell therapy for children--new medicines, new challenges?

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Buckland, Karen F; Bobby Gaspar, H

2014-06-01

The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery. Cell therapy clinical trials are underway for a variety of tissues including corneal, retinal and muscle repair and islet cell transplantation. Various cell therapy approaches are also being trialled to enhance the safety of bone marrow transplants, which should improve survival rates in childhood cancers and PIDs. Progress in genetic engineering of lymphocyte populations to target and kill cancerous cells is also described. If successful these ATMPs may enhance or replace the existing chemo-ablative therapy for several paediatric cancers. Emerging applications of gene therapy now include skin and neurological disorders such as epidermolysis bullosa, epilepsy and leukodystrophy. Gene therapy trials for haemophilia, muscular dystrophy and a range of metabolic disorders are underway. There is a vast array of potential advanced therapy medicinal products (ATMPs), and these are likely to be more cost effective than existing medicines. However, the first clinical trials have not been without setbacks and some of the key adverse events are discussed. Furthermore, the arrival of this novel class of therapies brings many new challenges for the healthcare industry. We present a summary of the key non-clinical factors required for successful delivery of these potential treatments. Technological advances

Combination of Heavy-ion radiotherapy and p53-gene therapy by radio-sensitizing promoter for glioma

International Nuclear Information System (INIS)

Oga, Masaru; Koshikawa, Nobuko; Takenaga, Keizo; Iwadate, Yasuo; Nojima, Kumie

2005-01-01

In this study we have investigated the anti-tumor effect of the combination of heavy-ion radiotherapy, inducing p53-independent apoptosis, and p53-gene therapy, inducing p53-dependent apoptosis for glioma. To enhance the p53-dependent apoptosis, we chose the strategy to utilize the heavy-ion irradiation itself as a ''trigger'' by using radio-sensitizing promoter-E9ns-2/CMV chimeric promoter (Scott et al:2003) in p53-gene therapy. First, EGFP reporter gene with E9ns-2/CMV chimeric promoter was transfected in C6 rat glioma cell-line and the transfected-cell bulk was irradiated at dose of 3, 5, 10 Gy respectively with charged carbon particle (290 MeV/nucleon). The light upregulation of EGFP was observed in 24 hours after 5 Gy irradiation. On the basis of this result, p53 gene with E9ns-2/CMV chimeric promoter was transfected in p53-mutant U373MG human glioma cell-line and the transfected-cell bulk was irradiated at dose of 5 Gy. There was, however, no obvious p53-upregulation at any time-point, so far. Further investigation is needed to clarify the appropriate experimental system. (author)

Experimental Validation of a Novel MRI-Compatible HIFU Device for the Treatment of Superficial Venous Insufficiency

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Salomir, Rares; Pichardo, Samuel; Petrusca, Lorena; Angel, Yves; Lacoste, François; Chapelon, Jean-Yves

2007-05-01

A novel High Intensity Focused Ultrasound (HIFU) probe has been designed for minimally-invasive treatment of valvular dysfunction in the saphenous vein, which is known to be the cause of superficial venous insufficiency (SVI) and varicose veins. Treating SVI with HIFU is possible, since venous tissue undergoes localized partial shrinkage when subjected to high temperature elevation. In a previous study in vitro we demonstrated that diameter shrinkage should be sufficient to restore valvular function, as this is done in the more aggressive approach known as external valvuloplasty. Numerical optimization using fast simulations of pressure field have led to a non-spherically shaped probe design with two HIFU elements that focus ultrasound uniformly over a line of length 7 mm, at a depth of 15 mm from the skin. A MR-compatible prototype of the probe has been constructed and this was characterized 1). by electroacustical mapping of the pressure field in water, and 2). by fast, high resolution MR thermal mapping ex vivo on fresh meat samples. Results were in good agreement with those predicted by an analytical approach and numerical simulations. Available experimental data suggest that a short sonication (less than 10 sec duration) should permit sufficient temperature elevation to obtain vein shrinkage. Further studies will be performed on surgically excised samples of human veins under MR thermal mapping in order to determine the optimal sonication parameters (duration and power level).

Translational control is a major contributor to hypoxia induced gene expression

International Nuclear Information System (INIS)

Beucken, Twan van den; Magagnin, Michael G.; Jutten, Barry; Seigneuric, Renaud; Lambin, Philippe; Koritzinsky, Marianne; Wouters, Bradly G.

2011-01-01

Background and purpose: Hypoxia is a common feature of solid tumors that is associated with an aggressive phenotype, resistance to therapy and poor prognosis. Major contributors to these adverse effects are the transcriptional program activated by the HIF family of transcription factors as well as the translational response mediated by PERK-dependent phosphorylation of eIF2α and inhibition of mTORC1 activity. In this study we determined the relative contribution of both transcriptional and translational responses to changes in hypoxia induced gene expression. Material and methods: Total and efficiently translated (polysomal) mRNA was isolated from DU145 prostate carcinoma cells that were exposed for up to 24 h of hypoxia ( 2 ). Changes in transcription and translation were assessed using affymetrix microarray technology. Results: Our data reveal an unexpectedly large contribution of translation control on both induced and repressed gene expression at all hypoxic time points, particularly during acute hypoxia (2-4 h). Gene ontology analysis revealed that gene classes like transcription and signal transduction are stimulated by translational control whereas expression of genes involved in cell growth and protein metabolism are repressed during hypoxic conditions by translational control. Conclusions: Our data indicate that translation influences gene expression during hypoxia on a scale comparable to that of transcription.

Design of HIFU Transducers to Generate Specific Nonlinear Ultrasound Fields

Science.gov (United States)

Khokhlova, Vera A.; Yuldashev, Petr V.; Rosnitskiy, Pavel B.; Maxwell, Adam D.; Kreider, Wayne; Bailey, Michael R.; Sapozhnikov, Oleg A.

Various clinical applications of high intensity focused ultrasound (HIFU) have different requirements on the pressure level and degree of nonlinear waveform distortion at the focus. Applications that utilize nonlinear waves with developed shocks are of growing interest, for example, for mechanical disintegration as well as for accelerated thermal ablation oftissue. In this work, an inverse problem of determining transducer parameters to enable formation of shockswith desired amplitude at the focus is solved. The solution was obtained by performing multipledirect simulations of the parabolic Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation for various parameters of the source. It is shown that results obtained within the parabolic approximation can be used to describe the focal region of single element spherical sourcesas well as complex transducer arrays. It is also demonstrated that the focal pressure level at which fully developed shocksare formed mainly depends on the focusing angle of the source and only slightly depends on its aperture and operating frequency. Using the simulation results, a 256-element HIFU array operating at 1.5 MHz frequency was designed for a specific application of boiling-histotripsy that relies on the presence of 90-100 MPa shocks at the focus. The size of the array elements and focusing angle of the array were chosen to satisfy technical limitations on the intensity at the array elements and desired shock amplitudes in the focal waveform. Focus steering capabilities of the array were analysed using an open-source T-Array software developed at Moscow State University.

Development of Viral Vectors for Gene Therapy for Chronic Pain

Directory of Open Access Journals (Sweden)

Yu Huang

2011-01-01

Full Text Available Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.

Gene therapy of cancer by vaccines carrying inserted immunostimulatory genes

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan

2007-01-01

Roč. 53, č. 3 (2007), s. 71-73 ISSN 0015-5500 Grant - others:EU-FP6 NoE Clinigene(XE) 018933; Liga proti rakovině, Praha(CZ) XX Institutional research plan: CEZ:AV0Z50520514 Keywords : gene therapy * immunostimulatory genes * vaccine Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.596, year: 2007

Cancer gene therapy targeting angiogenesis: An updated Review

Science.gov (United States)

Liu, Ching-Chiu; Shen, Zan; Kung, Hsiang-Fu; Lin, Marie CM

2006-01-01

Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy. PMID:17109514

DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease

Energy Technology Data Exchange (ETDEWEB)

Dupuy, Aurélie [Laboratory of Genetic Instability and Oncogenesis UMR8200CNRS, Institut Gustave Roussy and University Paris-Sud, Villejuif (France); Sarasin, Alain, E-mail: alain.sarasin@gustaveroussy.fr [Laboratory of Genetic Instability and Oncogenesis UMR8200CNRS, Institut Gustave Roussy and University Paris-Sud, Villejuif (France); Service de Génétique, Institut Gustave Roussy (France)

2015-06-15

Graphical abstract: - Highlights: • Full correction of mutation in the XPC gene by engineered nucleases. • Meganucleases and TALENs are inhibited by 5-MeC for inducing double strand breaks. • Gene therapy of XP cells is possible using homologous recombination for DSB repair. - Abstract: Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients.

DNA damage and gene therapy of xeroderma pigmentosum, a human DNA repair-deficient disease

International Nuclear Information System (INIS)

Dupuy, Aurélie; Sarasin, Alain

2015-01-01

Graphical abstract: - Highlights: • Full correction of mutation in the XPC gene by engineered nucleases. • Meganucleases and TALENs are inhibited by 5-MeC for inducing double strand breaks. • Gene therapy of XP cells is possible using homologous recombination for DSB repair. - Abstract: Xeroderma pigmentosum (XP) is a genetic disease characterized by hypersensitivity to ultra-violet and a very high risk of skin cancer induction on exposed body sites. This syndrome is caused by germinal mutations on nucleotide excision repair genes. No cure is available for these patients except a complete protection from all types of UV radiations. We reviewed the various techniques to complement or to correct the genetic defect in XP cells. We, particularly, developed the correction of XP-C skin cells using the fidelity of the homologous recombination pathway during repair of double-strand break (DSB) in the presence of XPC wild type sequences. We used engineered nucleases (meganuclease or TALE nuclease) to induce a DSB located at 90 bp of the mutation to be corrected. Expression of specific TALE nuclease in the presence of a repair matrix containing a long stretch of homologous wild type XPC sequences allowed us a successful gene correction of the original TG deletion found in numerous North African XP patients. Some engineered nucleases are sensitive to epigenetic modifications, such as cytosine methylation. In case of methylated sequences to be corrected, modified nucleases or demethylation of the whole genome should be envisaged. Overall, we showed that specifically-designed TALE-nuclease allowed us to correct a 2 bp deletion in the XPC gene leading to patient's cells proficient for DNA repair and showing normal UV-sensitivity. The corrected gene is still in the same position in the human genome and under the regulation of its physiological promoter. This result is a first step toward gene therapy in XP patients

Investor Outlook: Gene Therapy Picking up Steam; At a Crossroads.

Science.gov (United States)

Schimmer, Joshua; Breazzano, Steven

2016-09-01

The gene therapy field continues to pick up steam with recent successes in a number of different therapeutic indications that highlight the potential for the platform. As the field continues to make progress, a growing data set of long-term safety and efficacy data will continue to define gene therapy's role, determining ultimately how widely it may be used beyond rare, serious diseases with high unmet needs. New technologies often take unanticipated twists and turns as patient exposure accumulates, and gene therapy may be no exception. That said, with many diseases that have no other treatment options beyond gene therapy and that present considerable morbidity and mortality, the field appears poised to withstand some minor and even major bumps in the road should they emerge.

Gene Therapy in Cardiac Arrhythmias

OpenAIRE

Praveen, S.V; Francis, Johnson; Venugopal, K

2006-01-01

Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within the left bundle branch can provide stable heart rates. Genetic modification of the AV...

Real-time Monitoring of High Intensity Focused Ultrasound (HIFU) Ablation of In Vitro Canine Livers Using Harmonic Motion Imaging for Focused Ultrasound (HMIFU).

Science.gov (United States)

Grondin, Julien; Payen, Thomas; Wang, Shutao; Konofagou, Elisa E

2015-11-03

Harmonic Motion Imaging for Focused Ultrasound (HMIFU) is a technique that can perform and monitor high-intensity focused ultrasound (HIFU) ablation. An oscillatory motion is generated at the focus of a 93-element and 4.5 MHz center frequency HIFU transducer by applying a 25 Hz amplitude-modulated signal using a function generator. A 64-element and 2.5 MHz imaging transducer with 68kPa peak pressure is confocally placed at the center of the HIFU transducer to acquire the radio-frequency (RF) channel data. In this protocol, real-time monitoring of thermal ablation using HIFU with an acoustic power of 7 W on canine livers in vitro is described. HIFU treatment is applied on the tissue during 2 min and the ablated region is imaged in real-time using diverging or plane wave imaging up to 1,000 frames/second. The matrix of RF channel data is multiplied by a sparse matrix for image reconstruction. The reconstructed field of view is of 90° for diverging wave and 20 mm for plane wave imaging and the data are sampled at 80 MHz. The reconstruction is performed on a Graphical Processing Unit (GPU) in order to image in real-time at a 4.5 display frame rate. 1-D normalized cross-correlation of the reconstructed RF data is used to estimate axial displacements in the focal region. The magnitude of the peak-to-peak displacement at the focal depth decreases during the thermal ablation which denotes stiffening of the tissue due to the formation of a lesion. The displacement signal-to-noise ratio (SNRd) at the focal area for plane wave was 1.4 times higher than for diverging wave showing that plane wave imaging appears to produce better displacement maps quality for HMIFU than diverging wave imaging.

Gene Therapy with the Sleeping Beauty Transposon System.

Science.gov (United States)

Kebriaei, Partow; Izsvák, Zsuzsanna; Narayanavari, Suneel A; Singh, Harjeet; Ivics, Zoltán

2017-11-01

The widespread clinical implementation of gene therapy requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective, and economical manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient nonviral gene delivery approaches that are prevalent in ongoing clinical trials. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here, we review the most important aspects of using SB for gene therapy, including vectorization as well as genomic integration features. We also illustrate the path to successful clinical implementation by highlighting the application of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

Directory of Open Access Journals (Sweden)

Angelica Loskog

2015-11-01

Full Text Available Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription.

Science.gov (United States)

Gómez-Herreros, Fernando; Zagnoli-Vieira, Guido; Ntai, Ioanna; Martínez-Macías, María Isabel; Anderson, Rhona M; Herrero-Ruíz, Andrés; Caldecott, Keith W

2017-08-10

DNA double-strand breaks (DSBs) induced by abortive topoisomerase II (TOP2) activity are a potential source of genome instability and chromosome translocation. TOP2-induced DNA double-strand breaks are rejoined in part by tyrosyl-DNA phosphodiesterase 2 (TDP2)-dependent non-homologous end-joining (NHEJ), but whether this process suppresses or promotes TOP2-induced translocations is unclear. Here, we show that TDP2 rejoins DSBs induced during transcription-dependent TOP2 activity in breast cancer cells and at the translocation 'hotspot', MLL. Moreover, we find that TDP2 suppresses chromosome rearrangements induced by TOP2 and reduces TOP2-induced chromosome translocations that arise during gene transcription. Interestingly, however, we implicate TDP2-dependent NHEJ in the formation of a rare subclass of translocations associated previously with therapy-related leukemia and characterized by junction sequences with 4-bp of perfect homology. Collectively, these data highlight the threat posed by TOP2-induced DSBs during transcription and demonstrate the importance of TDP2-dependent non-homologous end-joining in protecting both gene transcription and genome stability.DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.

[Gene Therapy for Inherited RETINAL AND OPTIC NERVE Disorders: Current Knowledge].

Science.gov (United States)

Ďuďáková, Ľ; Kousal, B; Kolářová, H; Hlavatá, L; Lišková, P

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

Science.gov (United States)

Tuszynski, Mark H; Yang, Jennifer H; Barba, David; U, Hoi-Sang; Bakay, Roy A E; Pay, Mary M; Masliah, Eliezer; Conner, James M; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H

2015-10-01

genes, with resultant activation of cell signaling. No adverse pathological effects related to NGF were observed. These findings indicate that neurons of the degenerating brain retain the ability to respond to growth factors with axonal sprouting, cell hypertrophy, and activation of functional markers. Sprouting induced by NGF persists for 10 years after gene transfer. Growth factor therapy appears safe over extended periods and merits continued testing as a means of treating neurodegenerative disorders.

Gene therapy clinical trials worldwide to 2017: An update.

Science.gov (United States)

Ginn, Samantha L; Amaya, Anais K; Alexander, Ian E; Edelstein, Michael; Abedi, Mohammad R

2018-03-25

To date, almost 2600 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our November 2017 update, we have entries on 2597 trials undertaken in 38 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and the genes that have been transferred. Details of the analyses presented, and our searchable database are available via The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in gene therapy clinical trials around the world, and discuss key trends since the previous review, namely the use of chimeric antigen receptor T cells for the treatment of cancer and advancements in genome editing technologies, which have the potential to transform the field moving forward. Copyright © 2018 John Wiley & Sons, Ltd.

Bioethical conflicts of gene therapy: a brief critical review

Directory of Open Access Journals (Sweden)

José Ednésio da Cruz Freire

2014-12-01

Full Text Available Methods and techniques employed in gene therapy are reviewed in parallel with pertinent ethical conflicts. Clinical interventions based on gene therapy techniques preferentially use vectors for the transportation of therapeutic genes, however little is known about the potential risks and damages to the patient. Thus, attending carefully to the clinical complications arising as well as to security is essential. Despite the scientific and technological advances, there are still many uncertainties about the side effects of gene therapy. Moreover, there is a need, above all, to understand the principles of bioethics as both science and ethics, in accordance with its socioecological responsibility, in order to prioritize the health and welfare of man and nature, using properly natural resources and technology. Therefore, it is hard to determine objective results and to which extent the insertion of genes can affect the organism, as well as the ethical implication

Progress in nonviral gene therapy for breast cancer and what comes next?

Science.gov (United States)

Bottai, Giulia; Truffi, Marta; Corsi, Fabio; Santarpia, Libero

2017-05-01

The possibility of correcting defective genes and modulating gene expression through gene therapy has emerged as a promising treatment strategy for breast cancer. Furthermore, the relevance of tumor immune microenvironment in supporting the oncogenic process has paved the way for novel immunomodulatory applications of gene therapy. Areas covered: In this review, the authors describe the most relevant delivery systems, focusing on nonviral vectors, along with the description of the major approaches used to modify target cells, including gene transfer, RNA interference (RNAi), and epigenetic regulation. Furthermore, they highlight innovative therapeutic strategies and the application of gene therapy in clinical trials for breast cancer. Expert opinion: Gene therapy has the potential to impact breast cancer research. Further efforts are required to increase the clinical application of RNAi-based therapeutics, especially in combination with conventional treatments. Innovative strategies, including genome editing and stem cell-based systems, may contribute to translate gene therapy into clinical practice. Immune-based approaches have emerged as an attractive therapeutic opportunity for selected breast cancer patients. However, several challenges need to be addressed before considering gene therapy as an actual option for the treatment of breast cancer.

Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy.

Science.gov (United States)

Barar, Jaleh; Omidi, Yadollah

2013-01-01

It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called "tumor microenvironment (TME)", in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs) that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF) functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy

Directory of Open Access Journals (Sweden)

Jaleh Barar

2013-02-01

Full Text Available It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called “tumor microenvironment (TME”, in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders

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Vincenzo Cavalieri

2018-06-01

Full Text Available Lentiviruses have a number of molecular features in common, starting with the ability to integrate their genetic material into the genome of non-dividing infected cells. A peculiar property of non-primate lentiviruses consists in their incapability to infect and induce diseases in humans, thus providing the main rationale for deriving biologically safe lentiviral vectors for gene therapy applications. In this review, we first give an overview of non-primate lentiviruses, highlighting their common and distinctive molecular characteristics together with key concepts in the molecular biology of lentiviruses. We next examine the bioengineering strategies leading to the conversion of lentiviruses into recombinant lentiviral vectors, discussing their potential clinical applications in ophthalmological research. Finally, we highlight the invaluable role of animal organisms, including the emerging zebrafish model, in ocular gene therapy based on non-primate lentiviral vectors and in ophthalmology research and vision science in general.

Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases.

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Suen, Colin M; Mei, Shirley H J; Kugathasan, Lakshmi; Stewart, Duncan J

2013-10-01

Pulmonary arterial hypertension (PAH) is a devastating disease that, despite significant advances in medical therapies over the last several decades, continues to have an extremely poor prognosis. Gene therapy is a method to deliver therapeutic genes to replace defective or mutant genes or supplement existing cellular processes to modify disease. Over the last few decades, several viral and nonviral methods of gene therapy have been developed for preclinical PAH studies with varying degrees of efficacy. However, these gene delivery methods face challenges of immunogenicity, low transduction rates, and nonspecific targeting which have limited their translation to clinical studies. More recently, the emergence of regenerative approaches using stem and progenitor cells such as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) have offered a new approach to gene therapy. Cell-based gene therapy is an approach that augments the therapeutic potential of EPCs and MSCs and may deliver on the promise of reversal of established PAH. These new regenerative approaches have shown tremendous potential in preclinical studies; however, large, rigorously designed clinical studies will be necessary to evaluate clinical efficacy and safety. © 2013 American Physiological Society. Compr Physiol 3:1749-1779, 2013.

Gene therapy for Stargardt disease associated with ABCA4 gene.

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Han, Zongchao; Conley, Shannon M; Naash, Muna I

2014-01-01

Mutations in the photoreceptor-specific flippase ABCA4 lead to accumulation of the toxic bisretinoid A2E, resulting in atrophy of the retinal pigment epithelium (RPE) and death of the photoreceptor cells. Many blinding diseases are associated with these mutations including Stargardt's disease (STGD1), cone-rod dystrophy, retinitis pigmentosa (RP), and increased susceptibility to age-related macular degeneration. There are no curative treatments for any of these dsystrophies. While the monogenic nature of many of these conditions makes them amenable to treatment with gene therapy, the ABCA4 cDNA is 6.8 kb and is thus too large for the AAV vectors which have been most successful for other ocular genes. Here we review approaches to ABCA4 gene therapy including treatment with novel AAV vectors, lentiviral vectors, and non-viral compacted DNA nanoparticles. Lentiviral and compacted DNA nanoparticles in particular have a large capacity and have been successful in improving disease phenotypes in the Abca4 (-/-) murine model. Excitingly, two Phase I/IIa clinical trials are underway to treat patients with ABCA4-associated Startgardt's disease (STGD1). As a result of the development of these novel technologies, effective therapies for ABCA4-associated diseases may finally be within reach.

Current status of gene therapy for breast cancer: progress and challenges

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McCrudden CM

2014-11-01

Full Text Available Cian M McCrudden, Helen O McCarthySchool of Pharmacy, Queen’s University Belfast, Belfast, UKAbstract: Breast cancer is characterized by a series of genetic mutations and is therefore ideally placed for gene therapy intervention. The aim of gene therapy is to deliver a nucleic acid-based drug to either correct or destroy the cells harboring the genetic aberration. More recently, cancer gene therapy has evolved to also encompass delivery of RNA interference technologies, as well as cancer DNA vaccines. However, the bottleneck in creating such nucleic acid pharmaceuticals lies in the delivery. Deliverability of DNA is limited as it is prone to circulating nucleases; therefore, numerous strategies have been employed to aid with biological transport. This review will discuss some of the viral and nonviral approaches to breast cancer gene therapy, and present the findings of clinical trials of these therapies in breast cancer patients. Also detailed are some of the most recent developments in nonviral approaches to targeting in breast cancer gene therapy, including transcriptional control, and the development of recombinant, multifunctional bio-inspired systems. Lastly, DNA vaccines for breast cancer are documented, with comment on requirements for successful pharmaceutical product development.Keywords: breast cancer, gene therapy, nonviral, clinical trial

Communicating in context: a priority for gene therapy researchers.

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Robillard, Julie M

2015-03-01

History shows that public opinion of emerging biotechnologies has the potential to impact the research process through mechanisms such as funding and advocacy. It is critical, therefore, to consider public attitudes towards modern biotechnology such as gene therapy and more specifically towards the ethics of gene therapy, alongside advances in basic and clinical research. Research conducted through social media recently assessed how online users view the ethics of gene therapy and showed that while acceptability is high, significant ethical concerns remain. To address these concerns, the development of effective and evidence-based communication strategies that engage a wide range of stakeholders should be a priority for researchers.

Tumor tropism of intravenously injected human-induced pluripotent stem cell-derived neural stem cells and their gene therapy application in a metastatic breast cancer model.

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Yang, Jing; Lam, Dang Hoang; Goh, Sally Sallee; Lee, Esther Xingwei; Zhao, Ying; Tay, Felix Chang; Chen, Can; Du, Shouhui; Balasundaram, Ghayathri; Shahbazi, Mohammad; Tham, Chee Kian; Ng, Wai Hoe; Toh, Han Chong; Wang, Shu

2012-05-01

Human pluripotent stem cells can serve as an accessible and reliable source for the generation of functional human cells for medical therapies. In this study, we used a conventional lentiviral transduction method to derive human-induced pluripotent stem (iPS) cells from primary human fibroblasts and then generated neural stem cells (NSCs) from the iPS cells. Using a dual-color whole-body imaging technology, we demonstrated that after tail vein injection, these human NSCs displayed a robust migratory capacity outside the central nervous system in both immunodeficient and immunocompetent mice and homed in on established orthotopic 4T1 mouse mammary tumors. To investigate whether the iPS cell-derived NSCs can be used as a cellular delivery vehicle for cancer gene therapy, the cells were transduced with a baculoviral vector containing the herpes simplex virus thymidine kinase suicide gene and injected through tail vein into 4T1 tumor-bearing mice. The transduced NSCs were effective in inhibiting the growth of the orthotopic 4T1 breast tumor and the metastatic spread of the cancer cells in the presence of ganciclovir, leading to prolonged survival of the tumor-bearing mice. The use of iPS cell-derived NSCs for cancer gene therapy bypasses the sensitive ethical issue surrounding the use of cells derived from human fetal tissues or human embryonic stem cells. This approach may also help to overcome problems associated with allogeneic transplantation of other types of human NSCs. Copyright © 2012 AlphaMed Press.

Viral vectors for cystic fibrosis gene therapy: What does the future hold?

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Uta Griesenbach

2010-12-01

Full Text Available Uta Griesenbach1, Makoto Inoue2, Mamoru Hasegawa2, Eric WFW Alton11Department of Gene Therapy, Imperial College London, UK; The UK Cystic Fibrosis Gene Therapy Consortium; 2DNAVEC Corporation, Tsukuba, JapanAbstract: Gene transfer to the airway epithelium has been more difficult than originally anticipated, largely because of significant extra- and intracellular barriers in the lung. In general, viral vectors are more adapted to overcoming these barriers than nonviral gene transfer agents and are, therefore, more efficient in transferring genes into recipient cells. Viral vectors derived from adenovirus, adeno-associated virus, and Sendai virus, which all have a natural tropism for the airway epithelium, have been evaluated for cystic fibrosis (CF gene therapy. Although these vectors transduce airway epithelial cells efficiently, gene expression is transient and repeated administration is inefficient. They are, therefore, unlikely to be suitable for CF gene therapy. More recently, lentiviruses (LV have been assessed for lung gene transfer. In contrast to retroviruses, they transduce nondividing cells and randomly integrate into the genome. However, LVs do not have a natural tropism for the lung, and a significant amount of effort has been put into pseudotyping these vectors with proteins suitable for airway gene transfer. Several studies have shown that LV-mediated transduction leads to persistent gene expression (for the lifetime of the animal in the airways and, importantly, repeated administration is feasible. Thus, appropriately pseudotyped LV vectors are promising candidates for CF gene therapy. Here, we will review preclinical and clinical research related to viral CF gene therapy.Keywords: cystic fibrosis, gene therapy, adenovirus, AAV, lentivirus, Sendai virus

Combination of heavy-ion radiotherapy and p53-gene therapy by radio- and hypoxia-sensitizing promoter for glioma

International Nuclear Information System (INIS)

Oga, Masaru; Koshikawa, Nobuko; Takenaga, Keizo; Iwadate, Yasuo; Nojima, Kumie

2006-01-01

In this study we have started to investigate the anti-tumor effect of the combination of heavy-ion radiotherapy, inducing p53-independent apoptosis, and p53-gene therapy, inducing p53-dependent apoptosis for glioma. To enhance the p53-dependent apoptosis, we chose the strategy to utilize the heavy-ion irradiation itself as a ''trigger'' by using radio-sensitizing E 9ns-2 /cytomegalovirus (CMV) chimeric promoter (Scott et al: 2003) in p53-gene therapy. Our study in the first year, however, suggested the uselessness of E 9ns-2 /CMV chimeric promoter. Then we applied E 9ns-2 /Epo5/CMV-radio and hypoxia-sensitizing chimeric promoter to amplify p53 gene exopression. P53 gene with E 9ns2 /Epo5/CMV chimeric promoter was transfected in p53-mutant U373MG human glioma cell-line and the transfected-cell bulk was irradiated at dose of 1 Gy of high linear energy transfer (LET)-carbon ion beam or low-LET X-ray under various hypoxic conditions. The result suggested the possible role of 1 Gy of high LET-carbon ion beam as a ''useful trigger'' to enhance a selective anti-tumor effect toward glioma under hypoxic condition through amplification of p53 gene expression. (author)

CT-guided intratumoral gene therapy in non-small-cell lung cancer

International Nuclear Information System (INIS)

Kauczor, H.U.; Heussel, C.P.; Thelen, M.; Schuler, M.; Huber, C.; Weymarn, A. von; Bongartz, G.; Rochlitz, C.

1999-01-01

The objective of this study was to prove the principle of CT-guided gene therapy by intratumoral injection of a tumor suppressor gene as an alternative treatment approach of incurable non-small-cell lung cancer. In a prospective clinical phase I trial six patients with non-small-cell lung cancer and a mutation of the tumor suppressor gene p53 were treated by CT-guided intratumoral gene therapy. Ten milliliters of a vector solution (replication-defective adenovirus with complete wild-type p53 cDNA) were injected under CT guidance. In four cases the vector solution was completely applied to the tumor center, whereas in two cases 2 ml aliquots were injected into different tumor areas. For the procedure the scan room had been approved as a biosafety cabinet. Gene transfer was assessed by reverse transcription and polymerase chain reaction in biopsy specimens obtained under CT guidance 24-48 h after therapy. Potential therapeutic efficacy was evaluated on day 28 after treatment using spiral CT. The CT-guided gene therapy was easily performed in all six patients without intervention-related complications. Besides flu-like symptoms, no significant adverse effects of gene therapy were noted. Three of the four patients with central injection exhibited gene transfer in the posttreatment biopsy. Gene transfer could not be proven in the two patients with multiple 2 ml injections. After 28 days, four of the six patients showed stable disease at the treated tumor site, whereas other tumor manifestations progressed. Computed tomography-guided injections are an adequate and easy-to-perform procedure for intratumoral gene therapy. (orig.)

Gene therapy as a potential tool for treating neuroblastoma-a focused review.

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Kumar, M D; Dravid, A; Kumar, A; Sen, D

2016-05-01

Neuroblastoma, a solid tumor caused by rapid division of undifferentiated neuroblasts, is the most common childhood malignancy affecting children aged genes is restored to normalcy. Gene therapy is a powerful tool with the potential to inhibit the deleterious effects of oncogenes by inserting corrected/normal genes into the genome. Both viral and non-viral vector-based gene therapies have been developed and adopted to deliver the target genes into neuroblastoma cells. These attempts have given hope to bringing in a new regime of treatment against neuroblastoma. A few gene-therapy-based treatment strategies have been tested in limited clinical trials yielding some positive results. This mini review is an attempt to provide an overview of the available options of gene therapy to treat neuroblastoma.

Biosensor-controlled gene therapy/drug delivery with nanoparticles for nanomedicine

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Prow, Tarl W.; Rose, William A.; Wang, Nan; Reece, Lisa M.; Lvov, Yuri; Leary, James F.

2005-04-01

Nanomedicine involves cell-by-cell regenerative medicine, either repairing cells one at a time or triggering apoptotic pathways in cells that are not repairable. Multilayered nanoparticle systems are being constructed for the targeted delivery of gene therapy to single cells. Cleavable shells containing targeting, biosensing, and gene therapeutic molecules are being constructed to direct nanoparticles to desired intracellular targets. Therapeutic gene sequences are controlled by biosensor-activated control switches to provide the proper amount of gene therapy on a single cell basis. The central idea is to set up gene therapy "nanofactories" inside single living cells. Molecular biosensors linked to these genes control their expression. Gene delivery is started in response to a biosensor detected problem; gene delivery is halted when the cell response indicates that more gene therapy is not needed. Cell targeting of nanoparticles, both nanocrystals and nanocapsules, has been tested by a combination of fluorescent tracking dyes, fluorescence microscopy and flow cytometry. Intracellular targeting has been tested by confocal microscopy. Successful gene delivery has been visualized by use of GFP reporter sequences. DNA tethering techniques were used to increase the level of expression of these genes. Integrated nanomedical systems are being designed, constructed, and tested in-vitro, ex-vivo, and in small animals. While still in its infancy, nanomedicine represents a paradigm shift in thinking-from destruction of injured cells by surgery, radiation, chemotherapy to cell-by-cell repair within an organ and destruction of non-repairable cells by natural apoptosis.

Gene therapy in animal models of autosomal dominant retinitis pigmentosa

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Rossmiller, Brian; Mao, Haoyu

2012-01-01

Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

Building for Biology: A Gene Therapy Trial Infrastructure

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Samuel Taylor-Alexander

2017-06-01

Full Text Available In this article, we examine the construction of the infrastructure for a Phase II gene therapy trial for Cystic Fibrosis (CF. Tracing the development of the material technologies and physical spaces used in the trial, we show how the trial infrastructure took form at the uncertain intersection of scientific norms, built environments, regulatory negotiations, patienthood, and the biologies of both disease and therapy. We define infrastructures as material and immaterial (including symbols and affect composites that serve a selective distributive purpose and facilitate projects of making and doing. There is a politics to this distributive action, which is itself twofold, because whilst infrastructures enable and delimit the movement of matter, they also mediate the very activity for which they provide the grounds. An infrastructural focus allows us to show how purposeful connections are made in a context of epistemic and regulatory uncertainty. The gene therapy researchers were working in a context of multiple uncertainties, regarding not only how to do gene therapy, but also how to anticipate and enact ambiguous regulatory requirements in a context of limited resources (technical, spatial, and financial. At the same time, the trial infrastructure had to accommodate Cystic Fibrosis biology by bridging the gap between pathology and therapy. The consortium’s approach to treating CF required that they address concerns about contamination and safety while finding a way of getting a modified gene product into the lungs of the trial participants.

Prospects for Gene Therapy in the Fragile X Syndrome

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Rattazzi, Mario C.; LaFauci, Giuseppe; Brown, W. Ted

2004-01-01

Gene therapy is unarguably the definitive way to treat, and possibly cure, genetic diseases. A straightforward concept in theory, in practice it has proven difficult to realize, even when directed to easily accessed somatic cell systems. Gene therapy for diseases in which the central nervous system (CNS) is the target organ presents even greater…

Changes in rat spinal cord gene expression after inflammatory hyperalgesia of the joint and manual therapy.

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Ruhlen, Rachel L; Singh, Vineet K; Pazdernik, Vanessa K; Towns, Lex C; Snider, Eric J; Sargentini, Neil J; Degenhardt, Brian F

2014-10-01

Mobilization of a joint affects local tissue directly but may also have other effects that are mediated through the central nervous system. To identify differential gene expression in the spinal cords of rats with or without inflammatory joint injury after manual therapy or no treatment. Rats were randomly assigned to 1 of 4 treatment groups: no injury and no touch (NI/NT), injury and no touch (I/NT), no injury and manual therapy (NI/MT), and injury and manual therapy (I/MT). We induced acute inflammatory joint injury in the rats by injecting carrageenan into an ankle. Rats in the no-injury groups did not receive carrageenan injection. One day after injury, rats received manual therapy to the knee of the injured limb. Rats in the no-touch groups were anesthetized without receiving manual therapy. Spinal cords were harvested 30 minutes after therapy or no touch, and spinal cord gene expression was analyzed by microarray for 3 comparisons: NI/NT vs I/NT, I/MT vs I/NT, and NI/NT vs NI/MT. Three rats were assigned to each group. Of 38,875 expressed sequence tags, 755 were differentially expressed in the NI/NT vs I/NT comparison. For the other comparisons, no expressed sequence tags were differentially expressed. Cluster analysis revealed that the differentially expressed sequence tags were over-represented in several categories, including ion homeostasis (enrichment score, 2.29), transmembrane (enrichment score, 1.55), and disulfide bond (enrichment score, 2.04). An inflammatory injury to the ankle of rats caused differential expression of genes in the spinal cord. Consistent with other studies, genes involved in ion transport were among those affected. However, manual therapy to the knees of injured limbs or to rats without injury did not alter gene expression in the spinal cord. Thus, evidence for central nervous system mediation of manual therapy was not observed. © 2014 The American Osteopathic Association.

Natural Gene Therapy in Dystrophic Epidermolysis Bullosa

NARCIS (Netherlands)

van den Akker, Peter C.; Nijenhuis, Albertine; Hofstra, Robert M. W.; Jonkman, Marcel F.; Pasmooij, Anna M. G.; Meijer, G.

Background: Dystrophic epidermolysis bullosa is a genetic blistering disorder caused by mutations in the type VII collagen gene, COL7A1. In revertant mosaicism, germline mutations are corrected by somatic events resulting in a mosaic disease distribution. This "natural gene therapy" phenomenon long

A software tool for advanced MRgFUS prostate therapy planning and follow up

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van Straaten, Dörte; Hoogenboom, Martijn; van Amerongen, Martinus J.; Weiler, Florian; Issawi, Jumana Al; Günther, Matthias; Fütterer, Jurgen; Jenne, Jürgen W.

2017-03-01

US guided HIFU/FUS ablation for the therapy of prostate cancer is a clinical established method, while MR guided HIFU/FUS applications for prostate recently started clinical evaluation. Even if MRI examination is an excellent diagnostic tool for prostate cancer, it is a time consuming procedure and not practicable within an MRgFUS therapy session. The aim of our ongoing work is to develop software to support therapy planning and post-therapy follow-up for MRgFUS on localized prostate cancer, based on multi-parametric MR protocols. The clinical workflow of diagnosis, therapy and follow-up of MR guided FUS on prostate cancer was deeply analyzed. Based on this, the image processing workflow was designed and all necessary components, e.g. GUI, viewer, registration tools etc. were defined and implemented. The software bases on MeVisLab with several implemented C++ modules for the image processing tasks. The developed software, called LTC (Local Therapy Control) will register and visualize automatically all images (T1w, T2w, DWI etc.) and ADC or perfusion maps gained from the diagnostic MRI session. This maximum of diagnostic information helps to segment all necessary ROIs, e.g. the tumor, for therapy planning. Final therapy planning will be performed based on these segmentation data in the following MRgFUS therapy session. In addition, the developed software should help to evaluate the therapy success, by synchronization and display of pre-therapeutic, therapy and follow-up image data including the therapy plan and thermal dose information. In this ongoing project, the first stand-alone prototype was completed and will be clinically evaluated.

A gene expression profile indicative of early stage HER2 targeted therapy response.

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O'Neill, Fiona; Madden, Stephen F; Clynes, Martin; Crown, John; Doolan, Padraig; Aherne, Sinéad T; O'Connor, Robert

2013-07-01

Efficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies. Treatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change. In these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.

Trojan horse at cellular level for tumor gene therapies.

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Collet, Guillaume; Grillon, Catherine; Nadim, Mahdi; Kieda, Claudine

2013-08-10

Among innovative strategies developed for cancer treatments, gene therapies stand of great interest despite their well-known limitations in targeting, delivery, toxicity or stability. The success of any given gene-therapy is highly dependent on the carrier efficiency. New approaches are often revisiting the mythic trojan horse concept to carry therapeutic nucleic acid, i.e. DNAs, RNAs or small interfering RNAs, to pathologic tumor site. Recent investigations are focusing on engineering carrying modalities to overtake the above limitations bringing new promise to cancer patients. This review describes recent advances and perspectives for gene therapies devoted to tumor treatment, taking advantage of available knowledge in biotechnology and medicine. Copyright © 2013 Elsevier B.V. All rights reserved.

Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

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Weß, Ludger; Schnieders, Frank

2017-12-01

Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

Applications of Gene Editing Technologies to Cellular Therapies.

Science.gov (United States)

Rein, Lindsay A M; Yang, Haeyoon; Chao, Nelson J

2018-03-27

Hematologic malignancies are characterized by genetic heterogeneity, making classic gene therapy with a goal of correcting 1 genetic defect ineffective in many of these diseases. Despite initial tribulations, gene therapy, as a field, has grown by leaps and bounds with the recent development of gene editing techniques including zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeat (CRISPR) sequences and CRISPR-associated protein-9 (Cas9) nuclease or CRISPR/Cas9. These novel technologies have been applied to efficiently and specifically modify genetic information in target and effector cells. In particular, CRISPR/Cas9 technology has been applied to various hematologic malignancies and has also been used to modify and improve chimeric antigen receptor-modified T cells for the purpose of providing effective cellular therapies. Although gene editing is in its infancy in malignant hematologic diseases, there is much room for growth and application in the future. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Prospects for Foamy Viral Vector Anti-HIV Gene Therapy

Directory of Open Access Journals (Sweden)

Arun K. Nalla

2016-03-01

Full Text Available Stem cell gene therapy approaches for Human Immunodeficiency Virus (HIV infection have been explored in clinical trials and several anti-HIV genes delivered by retroviral vectors were shown to block HIV replication. However, gammaretroviral and lentiviral based retroviral vectors have limitations for delivery of anti-HIV genes into hematopoietic stem cells (HSC. Foamy virus vectors have several advantages including efficient delivery of transgenes into HSC in large animal models, and a potentially safer integration profile. This review focuses on novel anti-HIV transgenes and the potential of foamy virus vectors for HSC gene therapy of HIV.

Transduction of Oct6 or Oct9 gene concomitant with Myc family gene induced osteoblast-like phenotypic conversion in normal human fibroblasts.

Science.gov (United States)

Mizoshiri, N; Kishida, T; Yamamoto, K; Shirai, T; Terauchi, R; Tsuchida, S; Mori, Y; Ejima, A; Sato, Y; Arai, Y; Fujiwara, H; Yamamoto, T; Kanamura, N; Mazda, O; Kubo, T

2015-11-27

Osteoblasts play essential roles in bone formation and regeneration, while they have low proliferation potential. Recently we established a procedure to directly convert human fibroblasts into osteoblasts (dOBs). Transduction of Runx2 (R), Osterix (X), Oct3/4 (O) and L-myc (L) genes followed by culturing under osteogenic conditions induced normal human fibroblasts to express osteoblast-specific genes and produce calcified bone matrix both in vitro and in vivo Intriguingly, a combination of only two factors, Oct3/4 and L-myc, significantly induced osteoblast-like phenotype in fibroblasts, but the mechanisms underlying the direct conversion remains to be unveiled. We examined which Oct family genes and Myc family genes are capable of inducing osteoblast-like phenotypic conversion. As result Oct3/4, Oct6 and Oct9, among other Oct family members, had the capability, while N-myc was the most effective Myc family gene. The Oct9 plus N-myc was the best combination to induce direct conversion of human fibroblasts into osteoblast-like cells. The present findings may greatly contribute to the elucidation of the roles of the Oct and Myc proteins in osteoblast direct reprogramming. The results may also lead to establishment of novel regenerative therapy for various bone resorption diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model

International Nuclear Information System (INIS)

Xu, Yu; Liu, Zhengchun; Kong, Haiyan; Sun, Wenjie; Liao, Zhengkai; Zhou, Fuxiang; Xie, Conghua

2011-01-01

Highlights: → A novel chimeric promoter consisting of CArG element and hTERT promoter was developed. → The promoter was characterized with radiation-inducibility and tumor-specificity. → Suicide gene system driven by the promoter showed remarkable cytotoxicity in vitro. → Co-expression of IL12 enhanced the promoter mediated suicide gene therapy in vivo. -- Abstract: The human telomerase reverse transcriptase (hTERT) promoter has been widely used in target gene therapy of cancer. However, low transcriptional activity limited its clinical application. Here, we designed a novel dual radiation-inducible and tumor-specific promoter system consisting of CArG elements and the hTERT promoter, resulting in increased expression of reporter genes after gamma-irradiation. Therapeutic and side effects of adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic (IAA) system downstream of the chimeric promoter were evaluated in mice bearing Lewis lung carcinoma, combining with or without adenovirus-mediated interleukin 12 (IL12) gene driven by the cytomegalovirus promoter. The combination treatment showed more effective suppression of tumor growth than those with single agent alone, being associated with pronounced intratumoral T-lymphocyte infiltration and minor side effects. Our results suggest that the combination treatment with HRP/IAA system driven by the novel chimeric promoter and the co-expression of IL12 might be an effective and safe target gene therapy strategy of cancer.

Co-expression of interleukin 12 enhances antitumor effects of a novel chimeric promoter-mediated suicide gene therapy in an immunocompetent mouse model

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Xu, Yu, E-mail: xuyu1001@gmail.com [Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Liu, Zhengchun, E-mail: l135027@126.com [Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Kong, Haiyan, E-mail: suppleant@163.com [Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Sun, Wenjie, E-mail: wendy11240325@163.com [Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Liao, Zhengkai, E-mail: fastbeta@gmail.com [Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Zhou, Fuxiang, E-mail: happyzhoufx@sina.com [Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); Xie, Conghua, E-mail: chxie_65@hotmail.com [Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan 430071 (China); Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, 169 Donghu Road, Wuhan 430071 (China); and others

2011-09-09

Highlights: {yields} A novel chimeric promoter consisting of CArG element and hTERT promoter was developed. {yields} The promoter was characterized with radiation-inducibility and tumor-specificity. {yields} Suicide gene system driven by the promoter showed remarkable cytotoxicity in vitro. {yields} Co-expression of IL12 enhanced the promoter mediated suicide gene therapy in vivo. -- Abstract: The human telomerase reverse transcriptase (hTERT) promoter has been widely used in target gene therapy of cancer. However, low transcriptional activity limited its clinical application. Here, we designed a novel dual radiation-inducible and tumor-specific promoter system consisting of CArG elements and the hTERT promoter, resulting in increased expression of reporter genes after gamma-irradiation. Therapeutic and side effects of adenovirus-mediated horseradish peroxidase (HRP)/indole-3-acetic (IAA) system downstream of the chimeric promoter were evaluated in mice bearing Lewis lung carcinoma, combining with or without adenovirus-mediated interleukin 12 (IL12) gene driven by the cytomegalovirus promoter. The combination treatment showed more effective suppression of tumor growth than those with single agent alone, being associated with pronounced intratumoral T-lymphocyte infiltration and minor side effects. Our results suggest that the combination treatment with HRP/IAA system driven by the novel chimeric promoter and the co-expression of IL12 might be an effective and safe target gene therapy strategy of cancer.

Gene therapy in cystic fibrosis.

Science.gov (United States)

Flotte, T R; Laube, B L

2001-09-01

Theoretically, cystic fibrosis transmembrane conductance regulator (CFTR) gene replacement during the neonatal period can decrease morbidity and mortality from cystic fibrosis (CF). In vivo gene transfers have been accomplished in CF patients. Choice of vector, mode of delivery to airways, translocation of genetic information, and sufficient expression level of the normalized CFTR gene are issues that currently are being addressed in the field. The advantages and limitations of viral vectors are a function of the parent virus. Viral vectors used in this setting include adenovirus (Ad) and adeno-associated virus (AAV). Initial studies with Ad vectors resulted in a vector that was efficient for gene transfer with dose-limiting inflammatory effects due to the large amount of viral protein delivered. The next generation of Ad vectors, with more viral coding sequence deletions, has a longer duration of activity and elicits a lesser degree of cell-mediated immunity in mice. A more recent generation of Ad vectors has no viral genes remaining. Despite these changes, the problem of humoral immunity remains with Ad vectors. A variety of strategies such as vector systems requiring single, or widely spaced, administrations, pharmacologic immunosuppression at administration, creation of a stealth vector, modification of immunogenic epitopes, or tolerance induction are being considered to circumvent humoral immunity. AAV vectors have been studied in animal and human models. They do not appear to induce inflammatory changes over a wide range of doses. The level of CFTR messenger RNA expression is difficult to ascertain with AAV vectors since the small size of the vector relative to the CFTR gene leaves no space for vector-specific sequences on which to base assays to distinguish endogenous from vector-expressed messenger RNA. In general, AAV vectors appear to be safe and have superior duration profiles. Cationic liposomes are lipid-DNA complexes. These vectors generally have been

A suicide gene therapy approach to treat epidermolysis bullosa-associated skin cancer

International Nuclear Information System (INIS)

Gruber, C.

2009-01-01

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disease causing extensive blister formation within the basal membrane zone (BMZ) of the skin and mucous membranes. It is caused by premature STOP mutations in the COL7A1 gene, which is indispensable for proper skin assembling. RDEB is associated with the development of a highly malignant skin cancer (squamous cell carcinoma, SCC) in early adulthood that displays a life threatening complication within this patient group. To date, neither chemo- nor radiotherapies showed successful results and due to the high metastatic potential of RDEB SCC wide surgical excision is still favoured. In this study we could reveal a new promising cancer treatment using spliceosome mediated RNA trans-splicing (SMaRT) using a suicide gene therapy approach. First we identified the tumour marker gene MMP-9 expressed by RDEB SCC cells in cell culture which was used to generate various pre-mRNA trans-splicing molecules (PTM). PTMs are able to facilitate trans-splicing between a tumour target gene and a cell death inducing peptide/toxin, encoded by the PTM. As a consequence the toxin is expressed in cancer cells leading to the induction of cell death. This technique offers high specificity in cancer cell targeting compared to other conventional cDNA expression studies. Various trans-splicing molecules were pre-evaluated in a fluorescence screening model for their best trans-splicing efficiency with the target molecule. Herein we identified two potent PTMs (PTM BD0 and PTM BD6), that were further adapted for endogenous suicide studies by inserting the toxin streptolysin O. In two independent in vitro cell culture assays we were able to confirm that the trans-splicing molecules are able to induce expression of the toxin resulting in cell membrane permeabilization and increased cell death induction. The results indicate that SMaRT technology offers a new platform for a suicide gene therapy approach to treat malignant squamous cell

Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene.

Science.gov (United States)

Melo, Luis G; Agrawal, Reitu; Zhang, Lunan; Rezvani, Mojgan; Mangi, Abeel A; Ehsan, Afshin; Griese, Daniel P; Dell'Acqua, Giorgio; Mann, Michael J; Oyama, Junichi; Yet, Shaw-Fang; Layne, Matthew D; Perrella, Mark A; Dzau, Victor J

2002-02-05

Ischemia and oxidative stress are the leading mechanisms for tissue injury. An ideal strategy for preventive/protective therapy would be to develop an approach that could confer long-term transgene expression and, consequently, tissue protection from repeated ischemia/reperfusion injury with a single administration of a therapeutic gene. In the present study, we used recombinant adeno-associated virus (rAAV) as a vector for direct delivery of the cytoprotective gene heme oxygenase-1 (HO-1) into the rat myocardium, with the purpose of evaluating this strategy as a therapeutic approach for long-term protection from ischemia-induced myocardial injury. Human HO-1 gene (hHO-1) was delivered to normal rat hearts by intramyocardial injection. AAV-mediated transfer of the hHO-1 gene 8 weeks before acute coronary artery ligation and release led to a dramatic reduction (>75%) in left ventricular myocardial infarction. The reduction in infarct size was accompanied by decreases in myocardial lipid peroxidation and in proapoptotic Bax and proinflammatory interleukin-1beta protein abundance, concomitant with an increase in antiapoptotic Bcl-2 protein level. This suggested that the transgene exerts its cardioprotective effects in part by reducing oxidative stress and associated inflammation and apoptotic cell death. This study documents the beneficial therapeutic effect of rAAV-mediated transfer, before myocardial injury, of a cytoprotective gene that confers long-term myocardial protection from ischemia/reperfusion injury. Our data suggest that this novel "pre-event" gene transfer approach may provide sustained tissue protection from future repeated episodes of injury and may be beneficial as preventive therapy for patients with or at risk of developing coronary ischemic events.

The use of genes for performance enhancement: doping or therapy?

Directory of Open Access Journals (Sweden)

R.S. Oliveira

2011-12-01

Full Text Available Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM to enhance athletic performance. In such ‘gene doping’, exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO, vascular endothelial growth factor (VEGF, insulin-like growth factor type 1 (IGF-1, myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping.

The use of genes for performance enhancement: doping or therapy?

Science.gov (United States)

Oliveira, R S; Collares, T F; Smith, K R; Collares, T V; Seixas, F K

2011-12-01

Recent biotechnological advances have permitted the manipulation of genetic sequences to treat several diseases in a process called gene therapy. However, the advance of gene therapy has opened the door to the possibility of using genetic manipulation (GM) to enhance athletic performance. In such 'gene doping', exogenous genetic sequences are inserted into a specific tissue, altering cellular gene activity or leading to the expression of a protein product. The exogenous genes most likely to be utilized for gene doping include erythropoietin (EPO), vascular endothelial growth factor (VEGF), insulin-like growth factor type 1 (IGF-1), myostatin antagonists, and endorphin. However, many other genes could also be used, such as those involved in glucose metabolic pathways. Because gene doping would be very difficult to detect, it is inherently very attractive for those involved in sports who are prepared to cheat. Moreover, the field of gene therapy is constantly and rapidly progressing, and this is likely to generate many new possibilities for gene doping. Thus, as part of the general fight against all forms of doping, it will be necessary to develop and continually improve means of detecting exogenous gene sequences (or their products) in athletes. Nevertheless, some bioethicists have argued for a liberal approach to gene doping.

Adeno-associated virus for cystic fibrosis gene therapy