[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.

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.

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.

Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer--A preliminary report

International Nuclear Information System (INIS)

Teh, Bin S.; Aguilar-Cordova, Estuardo; Kernen, Kenneth; Chou, C.-C.; Shalev, Moshe; Vlachaki, Maria T.; Miles, Brian; Kadmon, Dov; Mai, W.-Y.; Caillouet, James; Davis, Maria; Ayala, Gustavo; Wheeler, Thomas; Brady, Jett; Carpenter, L. Steve; Lu, Hsin H.; Chiu, J. Kam; Woo, Shiao Y.; Thompson, Timothy; Butler, E. Brian

2001-01-01

Purpose: To report the preliminary results of a Phase I/II study combining radiotherapy and in situ gene therapy (adenovirus/herpes simplex virus thymidine kinase gene/valacyclovir) with or without hormonal therapy in the treatment of prostate cancer. Methods and Materials: Arm A: low-risk patients (T1-T2a, Gleason score <7, pretreatment PSA <10) were treated with combined radio-gene therapy. A mean dose of 76 Gy was delivered to the prostate with intensity-modulated radiotherapy. Arm B: high-risk patients (T2b-T3, Gleason score ≥7, pretreatment PSA ≥10) were treated with combined radio-gene therapy and hormonal therapy. Hormonal therapy was comprised of a 4-month leuprolide injection and 2-week use of flutamide. Arm C: Stage D1 (positive pelvic lymph node) patients received the same regimen as Arm B, with the additional 45 Gy to the pelvic lymphatics. Treatment-related toxicity was assessed using Cancer Therapy Evaluation Program common toxicity score and Radiation Therapy Oncology Group (RTOG) toxicity score. Results: Thirty patients (13 in Arm A, 14 in Arm B, and 3 in Arm C) completed the trial. Median follow-up was 5.5 months. Eleven patients (37%) developed flu-like symptoms (Cancer Therapy Evaluation Program Grade 1) of fatigue and chills/rigors after gene therapy injection but recovered within 24 h. Four patients (13%) and 2 patients (7%) developed Grade 1 and 2 fever, respectively. There was no patient with weight loss. One patient in Arm B developed Grade 3 elevation in liver enzyme, whereas 11 and 2 patients developed Grade 1 and 2 abnormal liver function tests. There was no Grade 2 or above hematologic toxicity. Three patients had transient rise in creatinine. There was no RTOG Grade 3 or above lower gastrointestinal toxicity. Toxicity levels were as follows: 4 patients (13%), Grade 2; 6 patients (20%), Grade 1; and 20 patients (67%), no toxicity. There was 1 patient with RTOG Grade 3 genitourinary toxicity, 12 patients (40%) with Grade 2, 8 patients

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.

Standards for gene therapy clinical trials based on pro-active risk assessment in a London NHS Teaching Hospital Trust.

Science.gov (United States)

Bamford, K B; Wood, S; Shaw, R J

2005-02-01

Conducting gene therapy clinical trials with genetically modified organisms as the vectors presents unique safety and infection control issues. The area is governed by a range of legislation and guidelines, some unique to this field, as well as those pertinent to any area of clinical work. The relevant regulations covering gene therapy using genetically modified vectors are reviewed and illustrated with the approach taken by a large teaching hospital NHS Trust. Key elements were Trust-wide communication and involvement of staff in a pro-active approach to risk management, with specific emphasis on staff training and engagement, waste management, audit and record keeping. This process has led to the development of proposed standards for clinical trials involving genetically modified micro-organisms.

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

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.

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.

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)

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

Gene therapy and angiogenesis in patients with coronary artery disease

DEFF Research Database (Denmark)

Kastrup, Jens

2010-01-01

-blind placebo-controlled trials could not confirm the initial high efficacy of either the growth factor protein or the gene therapy approaches observed in earlier small trials. The clinical studies so far have all been without any gene-related serious adverse events. Future trials will focus on whether...... an improvement in clinical results can be obtained with a cocktail of growth factors or by a combination of gene and stem cell therapy in patients with severe coronary artery disease, which cannot be treated effectively with current treatment strategies....... of VEGF and FGF in patients with coronary artery disease. The initial small and unblinded studies with either recombinant growth factor proteins or genes encoding growth factors were encouraging, demonstrating both clinical improvement and evidence of angiogenesis. However, subsequent larger double...

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

Science.gov (United States)

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

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.

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.

Gene Therapy

Science.gov (United States)

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 ...

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

Directory of Open Access Journals (Sweden)

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

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

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.

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.

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.

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.

Genes and Gene Therapy

Science.gov (United States)

... 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 ...

Risk of discontinuation of Advanced Therapy Medicinal Products clinical trials.

Science.gov (United States)

Hanna, Eve; Rémuzat, Cecile; Auquier, Pascal; Toumi, Mondher

2016-01-01

Advanced therapy medicinal products (ATMPs) constitute a class of innovative products that encompasses gene therapy, somatic cell therapy, and tissue-engineered products (TEP). There is an increased investment of commercial and non-commercial sponsors in this field and a growing number of ATMPs randomized clinical trials (RCT) and patients enrolled in such trials. RCT generate data to prove the efficacy of a new therapy, but the discontinuation of RCTs wastes scarce resources. Our objective is to identify the number and characteristics of discontinued ATMPs trials in order to evaluate the rate of discontinuation. We searched for ATMPs trials conducted between 1999 to June 2015 using three databases, which are Clinicaltrials.gov, the International Clinical Trials Registry Platform (ICTRP), and the EU Drug Regulating Authorities Clinical Trials (EudraCT). We selected the ATMPs trials after elimination of the duplicates. We identified the disease areas and the sponsors as commercial or non-commercial organizations. We classified ATMPs by type and trial status, that is, ongoing, completed, terminated, discontinued, and prematurely ended. Then, we calculated the rate of discontinuation. Between 1999 and June 2015, 143 withdrawn, terminated, or prematurely ended ATMPs clinical trials were identified. Between 1999 and June 2013, 474 ongoing and completed clinical trials were identified. Therefore, the rate of discontinuation of ATMPs trials is 23.18%, similar to that for non-ATMPs drugs in development. The probability of discontinuation is, respectively, 27.35, 16.28, and 16.34% for cell therapies, gene therapies, and TEP. The highest discontinuation rate is for oncology (43%), followed by cardiology (19.2%). It is almost the same for commercial and non-commercial sponsors; therefore, the discontinuation reason may not be financially driven. No failure risk rate per development phase is available for ATMPs. The discontinuation rate may prove helpful when assessing the

Gene and cell therapy for children — New medicines, new challenges?☆

Science.gov (United States)

Buckland, Karen F.; Bobby Gaspar, H.

2014-01-01

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

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.

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

[Gene therapy and cell transplantation for Parkinson's disease].

Science.gov (United States)

Muramatsu, Shin-ichi

2005-11-01

Increasing enthusiasm in the field of stem cell research is raising the hope of novel cell replacement therapies for Parkinson's disease (PD), but it also raises both scientific and ethical concerns. In most cases, dopaminergic cells are transplanted ectopically into the striatum instead of the substantia nigra. If the main mechanism underlying any observed functional recovery with these cell replacement therapies is restoration of dopaminergic neurotransmission, then viral vector-mediated gene delivery of dopamine-synthesizing enzymes is a more straight forward approach. The development of a recombinant adeno-associated viral (AAV) vector is making gene therapy for PD a feasible therapeutic option in the clinical arena. Efficient and long-term expression of genes for dopamine-synthesizing enzymes in the striatum restored local dopamine production and allowed behavioral recovery in animal models of PD. A clinical trial to evaluate the safety and efficacy of AAV vector-mediated gene transfer of aromatic L-amino acid decarboxylase, an enzyme that converts L-dopa to dopamine, is underway. With this strategy patients would still need to take L-dopa to control their PD symptoms, however, dopamine production could be regulated by altering the dose of L-dopa. Another AAV vector-based clinical trial is also ongoing in which the subthalamic nucleus is transduced to produce inhibitory transmitters.

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

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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.

Gene Therapy in Fanconi Anemia: A Matter of Time, Safety and Gene Transfer Tool Efficiency.

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Verhoeyen, Els; Roman-Rodriguez, Francisco Jose; Cosset, Francois-Loic; Levy, Camille; Rio, Paula

2017-01-01

Fanconi anemia (FA) is a rare genetic syndrome characterized by progressive marrow failure. Gene therapy by infusion of FA-corrected autologous hematopoietic stem cells (HSCs) may offer a potential cure since it is a monogenetic disease with mutations in the FANC genes, coding for DNA repair enzymes [1]. However, the collection of hCD34+-cells in FA patients implies particular challenges because of the reduced numbers of progenitor cells present in their bone marrow (BM) [2] or mobilized peripheral blood [3-5]. In addition, the FA genetic defect fragilizes the HSCs [6]. These particular features might explain why the first clinical trials using murine leukemia virus derived retroviral vectors conducted for FA failed to show engraftment of corrected cells. The gene therapy field is now moving towards the use of lentiviral vectors (LVs) evidenced by recent succesful clinical trials for the treatment of patients suffering from adrenoleukodystrophy (ALD) [7], β-thalassemia [8], metachromatic leukodystrophy [9] and Wiskott-Aldrich syndrome [10]. LV trials for X-linked severe combined immunodificiency and Fanconi anemia (FA) defects were recently initiated [11, 12]. Fifteen years of preclinical studies using different FA mouse models and in vitro research allowed us to find the weak points in the in vitro culture and transduction conditions, which most probably led to the initial failure of FA HSC gene therapy. In this review, we will focus on the different obstacles, unique to FA gene therapy, and how they have been overcome through the development of optimized protocols for FA HSC culture and transduction and the engineering of new gene transfer tools for FA HSCs. These combined advances in the field hopefully will allow the correction of the FA hematological defect in the near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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...

Application of HSVtk suicide gene to X-SCID gene therapy: Ganciclovir treatment offsets gene corrected X-SCID B cells

International Nuclear Information System (INIS)

Uchiyama, Toru; Kumaki, Satoru; Ishikawa, Yoshinori; Onodera, Masafumi; Sato, Miki; Du, Wei; Sasahara, Yoji; Tanaka, Nobuyuki; Sugamura, Kazuo; Tsuchiya, Shigeru

2006-01-01

Recently, a serious adverse effect of uncontrolled clonal T cell proliferation due to insertional mutagenesis of retroviral vector was reported in X-SCID gene therapy clinical trial. To offset the side effect, we have incorporated a suicide gene into therapeutic retroviral vector for selective elimination of transduced cells. In this study, B-cell lines from two X-SCID patients were transduced with bicistronic retroviral vector carrying human γc chain cDNA and Herpes simplex virus thymidine kinase gene. After confirmation of functional reconstitution of the γc chain, the cells were treated with ganciclovir (GCV). The γc chain positive cells were eliminated under low concentration without cytotoxicity on untransduced cells and have not reappeared at least for 5 months. Furthermore, the γc chain transduced cells were still sensitive to GCV after five months. These results demonstrated the efficacy of the suicide gene therapy although further in vivo studies are required to assess feasibility of this approach in clinical trial

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.

Genetic modification of hematopoietic stem cells: recent advances in the gene therapy of inherited diseases.

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Bueren, Juan A; Guenechea, Guillermo; Casado, José A; Lamana, María Luisa; Segovia, José C

2003-01-01

Hematopoietic stem cells constitute a rare population of precursor cells with remarkable properties for being used as targets in gene therapy protocols. The last years have been particularly productive both in the fields of gene therapy and stem cell biology. Results from ongoing clinical trials have shown the first unquestionable clinical benefits of immunodeficient patients transplanted with genetically modified autologous stem cells. On the other hand, severe side effects in a few patients treated with gene therapy have also been reported, indicating the usefulness of further improving the vectors currently used in gene therapy clinical trials. In the field of stem cell biology, evidence showing the plastic potential of adult hematopoietic stem cells and data indicating the multipotency of adult mesenchymal precursor cells have been presented. Also, the generation of embryonic stem cells by means of nuclear transfer techniques has appeared as a new methodology with direct implications in gene therapy.

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.

Terapia gênica Gene therapy

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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.

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.

Development of gene therapy: potential in severe combined immunodeficiency due to adenosine deaminase deficiency

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Claudia A Montiel-Equihua

2009-12-01

Full Text Available Claudia A Montiel-Equihua, Adrian J Thrasher, H Bobby GasparCentre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, London, UKAbstract: The history of stem cell gene therapy is strongly linked to the development of gene therapy for severe combined immunodeficiencies (SCID and especially adenosine deaminase (ADA-deficient SCID. Here we discuss the developments achieved in over two decades of clinical and laboratory research that led to the establishment of a protocol for the autologous transplant of retroviral vector-mediated gene-modified hematopoietic stem cells, which has proved to be both successful and, to date, safe. Patients in trials in three different countries have shown long-term immunological and metabolic correction. Nevertheless, improvements to the safety profile of viral vectors are underway and will undoubtedly reinforce the position of stem cell gene therapy as a treatment option for ADA-SCID.Keywords: adenosine deaminase, severe combined immunodeficiency, gene therapy, hematopoietic stem cell, retrovirus, clinical trial

Contemporary Animal Models For Human Gene Therapy Applications.

Science.gov (United States)

Gopinath, Chitra; Nathar, Trupti Job; Ghosh, Arkasubhra; Hickstein, Dennis Durand; Nelson, Everette Jacob Remington

2015-01-01

Over the past three decades, gene therapy has been making considerable progress as an alternative strategy in the treatment of many diseases. Since 2009, several studies have been reported in humans on the successful treatment of various diseases. Animal models mimicking human disease conditions are very essential at the preclinical stage before embarking on a clinical trial. In gene therapy, for instance, they are useful in the assessment of variables related to the use of viral vectors such as safety, efficacy, dosage and localization of transgene expression. However, choosing a suitable disease-specific model is of paramount importance for successful clinical translation. This review focuses on the animal models that are most commonly used in gene therapy studies, such as murine, canine, non-human primates, rabbits, porcine, and a more recently developed humanized mice. Though small and large animals both have their own pros and cons as disease-specific models, the choice is made largely based on the type and length of study performed. While small animals with a shorter life span could be well-suited for degenerative/aging studies, large animals with longer life span could suit longitudinal studies and also help with dosage adjustments to maximize therapeutic benefit. Recently, humanized mice or mouse-human chimaeras have gained interest in the study of human tissues or cells, thereby providing a more reliable understanding of therapeutic interventions. Thus, animal models are of great importance with regard to testing new vector technologies in vivo for assessing safety and efficacy prior to a gene therapy clinical trial.

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.

Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

Directory of Open Access Journals (Sweden)

B.E. Strauss

2007-05-01

Full Text Available A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

[Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

Science.gov (United States)

Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

2017-02-10

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

Factoring nonviral gene therapy into a cure for hemophilia A.

Science.gov (United States)

Gabrovsky, Vanessa; Calos, Michele P

2008-10-01

Gene therapy for hemophilia A has fallen short of success despite several clinical trials conducted over the past decade. Challenges to its success include vector immunogenicity, insufficient transgene expression levels of Factor VIII, and inhibitor antibody formation. Gene therapy has been dominated by the use of viral vectors, as well as the immunogenic and oncogenic concerns that accompany these strategies. Because of the complexity of viral vectors, the development of nonviral DNA delivery methods may provide an efficient and safe alternative for the treatment of hemophilia A. New types of nonviral strategies, such as DNA integrating vectors, and the success of several nonviral animal studies, suggest that nonviral gene therapy has curative potential and justifies its clinical development.

The gene therapy revolution in ophthalmology.

Science.gov (United States)

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.

Long-Term Effect of Gene Therapy on Leber's Congenital Amaurosis

OpenAIRE

Bainbridge, James W B; Mehat, Manjit S; Sundaram, Venki; Robbie, Scott J; Barker, Susie E; Ripamonti, Caterina; Georgiadis, Anastasios; Mowat, Freya M; Beattie, Stuart G; Gardner, Peter J; Feathers, Kecia L; Luong, Vy A; Yzer, Suzanne; Balaggan, Kamaljit; Viswanathan, Ananth

2015-01-01

Background Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. Methods We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, an...

Gene therapy for carcinoma of the breast: Therapeutic genetic correction strategies

International Nuclear Information System (INIS)

Obermiller, Patrice S; Tait, David L; Holt, Jeffrey T

2000-01-01

Gene therapy is a therapeutic approach that is designed to correct specific molecular defects that contribute to the cause or progression of cancer. Genes that are mutated or deleted in cancers include the cancer susceptibility genes p53 and BRCA1. Because mutational inactivation of gene function is specific to tumor cells in these settings, cancer gene correction strategies may provide an opportunity for selective targeting without significant toxicity for normal nontumor cells. Both p53 and BRCA1 appear to inhibit cancer cells that lack mutations in these genes, suggesting that the so-called gene correction strategies may have broader potential than initially believed. Increasing knowledge of cancer genetics has identified these and other genes as potential targets for gene replacement therapy. Initial patient trials of p53 and BRCA1 gene therapy have provided some indications of potential efficacy, but have also identified areas of basic and clinical research that are needed before these approaches may be widely used in patient care

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

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.)

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.

Investor Outlook: Significance of the Positive LCA2 Gene Therapy Phase III Results.

Science.gov (United States)

Schimmer, Joshua; Breazzano, Steven

2015-12-01

Spark Therapeutics recently reported positive phase III results for SPK-RPE65 targeting the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders), marking an important inflection point for the field of gene therapy. The results highlight the ability to successfully design and execute a randomized trial of a gene therapy and also reinforce the potentially predictive nature of early preclinical and clinical data. The results are expected to pave the way for the first approved gene therapy product in the United States and should sustain investor interest and confidence in gene therapy for many approaches, including retina targeting and beyond.

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

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

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

Gene therapy for Stargardt disease associated with ABCA4 gene.

Science.gov (United States)

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.

Evaluating Risks of Insertional Mutagenesis by DNA Transposons in Gene Therapy

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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

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

Gene doping: gene delivery for olympic victory

OpenAIRE

Gould, David

2012-01-01

With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted...

Clinical Trials

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Full Text Available ... for trials with cutting-edge approaches, such as gene therapy or new biological treatments. Health insurance and ... trials that involve high-risk procedures (such as gene therapy) or vulnerable patients (such as children). A ...

Pupillometric analysis for assessment of gene therapy in Leber Congenital Amaurosis patients

Directory of Open Access Journals (Sweden)

Melillo Paolo

2012-07-01

Full Text Available Abstract Background Objective techniques to assess the amelioration of vision in patients with impaired visual function are needed to standardize efficacy assessment in gene therapy trials for ocular diseases. Pupillometry has been investigated in several diseases in order to provide objective information about the visual reflex pathway and has been adopted to quantify visual impairment in patients with Leber Congenital Amaurosis (LCA. In this paper, we describe detailed methods of pupillometric analysis and a case study on three Italian patients affected by Leber Congenital Amaurosis (LCA involved in a gene therapy clinical trial at two follow-up time-points: 1 year and 3 years after therapy administration. Methods Pupillary light reflexes (PLR were measured in patients who had received a unilateral subretinal injection in a clinical gene therapy trial. Pupil images were recorded simultaneously in both eyes with a commercial pupillometer and related software. A program was generated with MATLAB software in order to enable enhanced pupil detection with revision of the acquired images (correcting aberrations due to the inability of these severely visually impaired patients to fixate, and computation of the pupillometric parameters for each stimulus. Pupil detection was performed through Hough Transform and a non-parametric paired statistical test was adopted for comparison. Results The developed program provided correct pupil detection also for frames in which the pupil is not totally visible. Moreover, it provided an automatic computation of the pupillometric parameters for each stimulus and enabled semi-automatic revision of computerized detection, eliminating the need for the user to manually check frame by frame. With reference to the case study, the amplitude of pupillary constriction and the constriction velocity were increased in the right (treated eye compared to the left (untreated eye at both follow-up time-points, showing stability of

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

Alzheimer 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 patients with AD. We present postmortem findings in 10 patients with survival times ranging from 1 to 10 years after treatment. To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. Patients in this anatomicopathological study were enrolled in clinical trials from March 2001 to October 2012 at the University of California, San Diego, Medical Center in La Jolla. Ten patients with early AD underwent NGF gene therapy using ex vivo or in vivo gene transfer. The brains of all 8 patients in the first phase 1 ex vivo trial and of 2 patients in a subsequent phase 1 in vivo trial were examined. Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In 2 patients, NGF protein levels were measured by enzyme-linked immunosorbent assay. Among 10 patients, degenerating neurons in the AD brain responded to NGF. All patients exhibited a trophic response to NGF in the form of axonal sprouting toward the NGF source. Comparing treated and nontreated sides of the brain in 3 patients who underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P < .05). Activation of cellular signaling and functional markers was present in 2 patients who underwent adeno-associated viral vectors (serotype 2)-mediated NGF gene transfer. Neurons exhibiting tau pathology and neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic

Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

Science.gov (United States)

Alton, Eric W F W; Armstrong, David K; Ashby, Deborah; Bayfield, Katie J; Bilton, Diana; Bloomfield, Emily V; Boyd, A Christopher; Brand, June; Buchan, Ruaridh; Calcedo, Roberto; Carvelli, Paula; Chan, Mario; Cheng, Seng H; Collie, D David S; Cunningham, Steve; Davidson, Heather E; Davies, Gwyneth; Davies, Jane C; Davies, Lee A; Dewar, Maria H; Doherty, Ann; Donovan, Jackie; Dwyer, Natalie S; Elgmati, Hala I; Featherstone, Rosanna F; Gavino, Jemyr; Gea-Sorli, Sabrina; Geddes, Duncan M; Gibson, James S R; Gill, Deborah R; Greening, Andrew P; Griesenbach, Uta; Hansell, David M; Harman, Katharine; Higgins, Tracy E; Hodges, Samantha L; Hyde, Stephen C; Hyndman, Laura; Innes, J Alastair; Jacob, Joseph; Jones, Nancy; Keogh, Brian F; Limberis, Maria P; Lloyd-Evans, Paul; Maclean, Alan W; Manvell, Michelle C; McCormick, Dominique; McGovern, Michael; McLachlan, Gerry; Meng, Cuixiang; Montero, M Angeles; Milligan, Hazel; Moyce, Laura J; Murray, Gordon D; Nicholson, Andrew G; Osadolor, Tina; Parra-Leiton, Javier; Porteous, David J; Pringle, Ian A; Punch, Emma K; Pytel, Kamila M; Quittner, Alexandra L; Rivellini, Gina; Saunders, Clare J; Scheule, Ronald K; Sheard, Sarah; Simmonds, Nicholas J; Smith, Keith; Smith, Stephen N; Soussi, Najwa; Soussi, Samia; Spearing, Emma J; Stevenson, Barbara J; Sumner-Jones, Stephanie G; Turkkila, Minna; Ureta, Rosa P; Waller, Michael D; Wasowicz, Marguerite Y; Wilson, James M; Wolstenholme-Hogg, Paul

2015-09-01

Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in

Clinical Trials

Medline Plus

Full Text Available ... for trials with cutting-edge approaches, such as gene therapy or new biological treatments. Health insurance and health ... trials that involve high-risk procedures (such as gene therapy) or vulnerable patients (such as children). A DSMB's ...

Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

Energy Technology Data Exchange (ETDEWEB)

Fillat, Cristina, E-mail: cristina.fillat@crg.es; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano [Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomedica de Barcelona-PRBB and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona (Spain)

2011-01-18

The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

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

Place of the nuclear medicine in the clinical development of the gene therapy

International Nuclear Information System (INIS)

Crochet, T.; Vis, J. de; Vincent, D.; Zanca, M.

2006-01-01

Although gene therapy has been proposed first for genetic diseases, its concept has been extended to many acquired diseases, owing to a better understanding of pathology at a molecular level. Overall, very few trials have shown to be efficient, and safety concerns have emerged, as a result of several patients deaths. There is a need for new techniques able to improve both the knowledge of the therapeutic gene fate once administered and the early detection of events likely to lead to serious adverse events. In vivo imaging of a reporter gene associated with the therapeutic one is certainly the most promising technique for these goals. Among available imaging modalities, nuclear imaging is the most likely to be applied to patients. This review begins with a summary of current knowledge about the steps that a therapeutic gene has to cross from vector delivery to appropriate expression in target cells. We show how gene imaging could allow to investigate many pitfalls of trials by providing a better understanding of these steps in patients. The reporter genes available for nuclear imaging are presented in the second section, through animal studies. Then, relevant examples of clinical trials are presented. These include cancer (suicide gene therapy and adoptive immunotherapy), ischemic heart diseases and cystic fibrosis. The results are commented with emphasis on the role of nuclear imaging to address the questions raised by these studies, and imaging studies carried out on animals or patients for the corresponding diseases or organs are presented. The results obtained in animal studies warrant the introduction of gene imaging in clinical trials. (authors)

The Role of Gene Therapy in the Treatment of Retinal Diseases: A Review.

Science.gov (United States)

Campa, C; Gallenga, C E; Bolletta, E; Perri, P

2017-01-01

Gene therapy represents the therapeutic delivery of nucleic acid polymers into patient cells with the aim of treating an underlying disease. Over the past 2 decades this new therapy has made substantial progress owing to better understanding of the pathobiologic basis of various diseases coupled with growth of gene transfer biotechnologies. The eye, in particular, represents a suitable target for such therapy due to the immune privilege provided by the blood-ocular barrier, the ability to directly visualize, access and locally treat the cells and the minimal amount of vector needed given the size of this organ. It is not surprising therefore that several clinical trials are now ongoing in this field. The purpose of this review was to provide an update on gene therapy for retinal diseases, discussing differences in treatment strategies, vector designs and surgical techniques. Research was performed on PubMed, ClinicalTrials.gov, and Home Genetic Reference. We additionally utilized the internet database for genetics of retinal diseases, the portal for rare diseases and orphan drugs and the NCBI database Online Mendelian Inheritance in Man. No restriction was applied on the language of publications. We present the available results of current active clinical trials for inherited retinal disease such as Leber's congenital amaurosis type 2, choroideremia, Stargardt disease, achromatopsia and juvenile X-linked retinoschisis. We also illustrate a new approach of this therapy for the treatment of much more common ocular diseases such as age-related macular degeneration and diabetic retinopathy. Gene therapy represents an emerging and promising therapeutic approach for the treatment not only of rare inherited retinal diseases but also much more common retinal pathologies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Historical Perspective on the Current Renaissance for Hematopoietic Stem Cell Gene Therapy.

Science.gov (United States)

Kohn, Donald B

2017-10-01

Gene therapy using hematopoietic stem cells (HSC) has developed over the past 3 decades, with progressive improvements in the efficacy and safety. Autologous transplantation of HSC modified with murine gammaretroviral vectors first showed clinical benefits for patients with several primary immune deficiencies, but some of these patients suffered complications from vector-related genotoxicity. Lentiviral vectors have been used recently for gene addition to HSC and have yielded clinical benefits for primary immune deficiencies, metabolic diseases, and hemoglobinopathies, without vector-related complications. Gene editing using site-specific endonucleases is emerging as a promising technology for gene therapy and is moving into clinical trials. Copyright © 2017 Elsevier Inc. All rights reserved.

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.)

Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

Directory of Open Access Journals (Sweden)

Christian Bressy

2017-06-01

Full Text Available Oncolytic virus (OV therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53 or another p53 family member (TP63 or TP73 were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.

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

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.

Recent Advancements in Gene Therapy for Hereditary Retinal Dystrophies

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Ayşe Öner

2017-12-01

Full Text Available Hereditary retinal dystrophies (HRDs are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision, and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family, highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been proposed as potentially efficacious therapies. Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Dozens of promising proofs of concept have been obtained in animal models of HRDs and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. This review summarizes the clinical development of retinal gene therapy.

A guide to approaching regulatory considerations for lentiviral-mediated gene therapies.

Science.gov (United States)

White, Michael; Whittaker, Roger; Stoll, Elizabeth Ann

2017-06-12

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well-characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is non-pathogenic and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations, and how they are administered in the United Kingdom, although many of the principles will be similar for other regions including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarises the extant regulatory guidance for gene therapies, categorised as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.

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

Science.gov (United States)

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.

Gene therapy and genome surgery in the retina.

Science.gov (United States)

DiCarlo, James E; Mahajan, Vinit B; Tsang, Stephen H

2018-06-01

Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

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.

Breast Cancer Gene Therapy: Development of Novel Non-Invasive Magnetic Resonance Assay to Optimize Efficacy

National Research Council Canada - National Science Library

Mason, Ralph P

2007-01-01

Gene therapy holds great promise for treatment of breast cancer. In particular clinical trials are underway to apply therapeutic genes related to pro-drug activation or to modulate the activity of oncogenes by blocking promoter sites...

Gene therapy for inherited retinal degenerations: initial successes and future challenges

Science.gov (United States)

Gupta, Priya R.; Huckfeldt, Rachel M.

2017-10-01

Inherited retinal degenerations are a clinically and genetically heterogeneous group of conditions that have historically shared an untreatable course. In recent years, however, a wide range of therapeutic strategies have demonstrated efficacy in preclinical studies and entered clinical trials with a common goal of improving visual function for patients affected with these conditions. Gene therapy offers a particularly elegant and precise opportunity to target the causative genetic mutations underlying these monogenic diseases. The present review will provide an overview of gene therapy with particular emphasis on key clinical results to date and challenges for the future.

The potential for tumor suppressor gene therapy in head and neck cancer.

Science.gov (United States)

Birkeland, Andrew C; Ludwig, Megan L; Spector, Matthew E; Brenner, J Chad

2016-01-01

Head and neck squamous cell carcinoma remains a highly morbid and fatal disease. Importantly, genomic sequencing of head and neck cancers has identified frequent mutations in tumor suppressor genes. While targeted therapeutics increasingly are being investigated in head and neck cancer, the majority of these agents are against overactive/overexpressed oncogenes. Therapy to restore lost tumor suppressor gene function remains a key and under-addressed niche in trials for head and neck cancer. Recent advances in gene editing have captured the interest of both the scientific community and the public. As our technology for gene editing and gene expression modulation improves, addressing lost tumor suppressor gene function in head and neck cancers is becoming a reality. This review will summarize new techniques, challenges to implementation, future directions, and ethical ramifications of gene therapy in head and neck cancer.

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…

Long-term effect of gene therapy on Leber's congenital amaurosis.

Science.gov (United States)

Bainbridge, James W B; Mehat, Manjit S; Sundaram, Venki; Robbie, Scott J; Barker, Susie E; Ripamonti, Caterina; Georgiadis, Anastasios; Mowat, Freya M; Beattie, Stuart G; Gardner, Peter J; Feathers, Kecia L; Luong, Vy A; Yzer, Suzanne; Balaggan, Kamaljit; Viswanathan, Ananth; de Ravel, Thomy J L; Casteels, Ingele; Holder, Graham E; Tyler, Nick; Fitzke, Fred W; Weleber, Richard G; Nardini, Marko; Moore, Anthony T; Thompson, Debra A; Petersen-Jones, Simon M; Michaelides, Michel; van den Born, L Ingeborgh; Stockman, Andrew; Smith, Alexander J; Rubin, Gary; Ali, Robin R

2015-05-14

Mutations in RPE65 cause Leber's congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

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)

Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease.

Science.gov (United States)

Rowland, Nathan C; Starr, Philip A; Larson, Paul S; Ostrem, Jill L; Marks, William J; Lim, Daniel A

2015-02-01

Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain. © 2014 International Parkinson and Movement Disorder Society.

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)

Science.gov (United States)

... 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 ...

Gene therapy for inherited retinal and optic nerve degenerations.

Science.gov (United States)

Moore, Nicholas A; Morral, Nuria; Ciulla, Thomas A; Bracha, Peter

2018-01-01

The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

Clinical Trials of Immunogene Therapy for Spontaneous Tumors in Companion Animals

Directory of Open Access Journals (Sweden)

Gerardo Claudio Glikin

2014-01-01

Full Text Available Despite the important progress obtained in the treatment of some pets’ malignancies, new treatments need to be developed. Being critical in cancer control and progression, the immune system’s appropriate modulation may provide effective therapeutic options. In this review we summarize the outcomes of published immunogene therapy veterinary clinical trials reported by many research centers. A variety of tumors such as canine melanoma, soft tissue sarcomas, osteosarcoma and lymphoma, feline fibrosarcoma, and equine melanoma were subjected to different treatment approaches. Both viral and mainly nonviral vectors were used to deliver gene products as cytokines, xenogeneic tumor associated antigens, specific ligands, and proapoptotic regulatory factors. In some cases autologous, allogenic, or xenogeneic transgenic cytokine producing cells were assayed. In general terms, minor or no adverse collateral effects appeared during this kind of therapies and treated patients usually displayed a better course of the disease (longer survival, delayed or suppressed recurrence or metastatic spread, and improvement of the quality of life. This suggests the utility of these methodologies as standard adjuvant treatments. The encouraging outcomes obtained in companion animals support their ready application in veterinary clinical oncology and serve as preclinical proof of concept and safety assay for future human gene therapy trials.

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

Oversight and Management of a Cell Therapy Clinical Trial Network: Experience and Lessons Learned

OpenAIRE

Moyé, Lemuel A.; Sayre, Shelly L.; Westbrook, Lynette; Jorgenson, Beth C.; Handberg, Eileen; Anwaruddin, Saif; Wagner, Kristi A.; Skarlatos, Sonia I.

2011-01-01

The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This arti...

Gene transfer strategies for improving radiolabeled peptide imaging and therapy

International Nuclear Information System (INIS)

Rogers, B.E.; Buchsbaum, D.J.; Zinn, K.R.

2000-01-01

Utilization of molecular biology techniques offers attractive options in nuclear medicine for improving cancer imaging and therapy with radiolabeled peptides. Two of these options include utilization of phage-panning to identify novel tumor specific peptides or single chain antibodies and gene transfer techniques to increase the antibodies and gene transfer techniques to increase the number of antigen/receptor sites expressed on malignant cells. The group has focused on the latter approach for improving radiolabeled peptide imaging and therapy. The most widely used gene transfer vectors in clinical gene therapy trials include retrovirus, cationic lipids and adenovirus. It has been utilized adenovirus vectors for gene transfer because of their ability to accomplish efficient in vivo gene transfer. Adenovirus vectors encoding the genes for a variety of antigens/receptors (carcinoembryonic antigen, gastrin-releasing peptide receptor, somatostatin receptor subtype 2 (SSTr2) have all shown that their expression is increased on cancer cells both in vitro and in vivo following adenovirus infection. Of particular interest has been the adenovirus encoding for SSTr2 (AdCMVSSTr2). Various radioisotopes have been attached to somatostatin analogues for imaging and therapy of SSTr2-positive tumors both clinically and in animal models. The use of these analogues in combination with AdCMVSSTr2 is a promising approach for improving the detection sensitivity and therapeutic efficacy of these radiolabeled peptides against solid tumors. In addition, it has been proposed the use of SSTr2 as a marker for imaging the expression of another cancer therapeutic transgene (e.g. cytosine deaminase, thymidine kinase) encoded within the same vector. This would allow for non-invasive monitoring of gene delivery to tumor sites

Test-Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial.

Science.gov (United States)

Parker, Maria A; Choi, Dongseok; Erker, Laura R; Pennesi, Mark E; Yang, Paul; Chegarnov, Elvira N; Steinkamp, Peter N; Schlechter, Catherine L; Dhaenens, Claire-Marie; Mohand-Said, Saddek; Audo, Isabelle; Sahel, Jose; Weleber, Richard G; Wilson, David J

2016-10-01

The goal of this analysis was to determine the test-retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial. Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic ABCA4 mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less. Functional visual evaluations included: best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, semiautomated kinetic perimetry (SKP) using isopters I4e, III4e, and V4e, hill of vision (HOV) calculated from static visual fields (SVF) by using a 184n point centrally condensed grid with the stimulus size V test target. Retinal structural changes such as central macular thickness and macular volume were assessed by spectral-domain optical coherence tomography (SD-OCT). Repeatability coefficients (RC) and 95% confidential intervals (CI) were calculated for each parameter using a hierarchical mixed-effects model and bootstrapping. Criteria for statistically significant changes for various parameters were found to be the following: BCVA letter score (8 letters), SKP isopters I4e, III4e, and V4e (3478.85; 2488.02 and 2622.46 deg 2 , respectively), SVF full volume HOV (V TOT, 14.62 dB-sr), central macular thickness, and macular volume (4.27 μm and 0.15 mm 3 , respectively). This analysis provides important information necessary to determine if significant changes are occurring in structural and functional assessments commonly used to measure disease progression in this cohort of patients with STGD. Moreover, this information is useful for future trials assessing safety and efficacy of treatments in STGD. Determination of variability of functional and structural measures in participants with advanced stages of

Test–Retest Variability of Functional and Structural Parameters in Patients with Stargardt Disease Participating in the SAR422459 Gene Therapy Trial

Science.gov (United States)

Parker, Maria A.; Choi, Dongseok; Erker, Laura R.; Pennesi, Mark E.; Yang, Paul; Chegarnov, Elvira N.; Steinkamp, Peter N.; Schlechter, Catherine L.; Dhaenens, Claire-Marie; Mohand-Said, Saddek; Audo, Isabelle; Sahel, Jose; Weleber, Richard G.; Wilson, David J.

2016-01-01

Purpose The goal of this analysis was to determine the test–retest variability of functional and structural measures from a cohort of patients with advanced forms of Stargardt Disease (STGD) participating in the SAR422459 (NCT01367444) gene therapy clinical trial. Methods Twenty-two participants, aged 24 to 66, diagnosed with advanced forms of STGD, with at least one pathogenic ABCA4 mutation on each chromosome participating in the SAR422459 (NCT01367444) gene therapy clinical trial, were screened over three visits within 3 weeks or less. Functional visual evaluations included: best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score, semiautomated kinetic perimetry (SKP) using isopters I4e, III4e, and V4e, hill of vision (HOV) calculated from static visual fields (SVF) by using a 184n point centrally condensed grid with the stimulus size V test target. Retinal structural changes such as central macular thickness and macular volume were assessed by spectral-domain optical coherence tomography (SD-OCT). Repeatability coefficients (RC) and 95% confidential intervals (CI) were calculated for each parameter using a hierarchical mixed-effects model and bootstrapping. Results Criteria for statistically significant changes for various parameters were found to be the following: BCVA letter score (8 letters), SKP isopters I4e, III4e, and V4e (3478.85; 2488.02 and 2622.46 deg2, respectively), SVF full volume HOV (VTOT, 14.62 dB-sr), central macular thickness, and macular volume (4.27 μm and 0.15 mm3, respectively). Conclusions This analysis provides important information necessary to determine if significant changes are occurring in structural and functional assessments commonly used to measure disease progression in this cohort of patients with STGD. Moreover, this information is useful for future trials assessing safety and efficacy of treatments in STGD. Translational Relevance Determination of variability of functional and

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

Improvement and decline in vision with gene therapy in childhood blindness.

Science.gov (United States)

Jacobson, Samuel G; Cideciyan, Artur V; Roman, Alejandro J; Sumaroka, Alexander; Schwartz, Sharon B; Heon, Elise; Hauswirth, William W

2015-05-14

Retinal gene therapy for Leber's congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00481546.).

Gene Therapy With Regulatory T Cells: A Beneficial Alliance

Directory of Open Access Journals (Sweden)

Moanaro Biswas

2018-03-01

Full Text Available Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs are critical for tolerance induction to the transgene product and in some cases the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product and concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve a sustained transgene expression. Furthermore, techniques to engineer antigen-specific Treg cell populations, either through reprogramming conventional CD4+ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in preclinical studies. Thus, based upon these observations and the successful use of chimeric (IgG-based antigen receptors (CARs in antigen-specific effector T cells, different types of CAR-Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article.

Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy.

Science.gov (United States)

Al-Zaidy, Samiah A; Sahenk, Zarife; Rodino-Klapac, Louise R; Kaspar, Brian; Mendell, Jerry R

2015-09-02

Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin.

Place of the nuclear medicine in the clinical development of the gene therapy; Place de la medecine nucleaire dans le developpement clinique de la therapie genique

Energy Technology Data Exchange (ETDEWEB)

Crochet, T. [Montpellier-1 Univ., 34 (France); Vis, J. de [Centre Hospitalier Universitaire, Hopital Saint Eloi, Institut de Recherche en Biotherapie, 34 - Montpellier (France); Vincent, D. [Centre Hospitalier Universitaire de Nimes, Service de Medecine Interne, Hopital Caremeau, 30 - Nimes (France); Zanca, M. [Centre Hospitalier Universitaire, Hopital Guy de Chauliac, Service de Medecine Nucleaire, 34 - Montpellier (France)

2006-10-15

Although gene therapy has been proposed first for genetic diseases, its concept has been extended to many acquired diseases, owing to a better understanding of pathology at a molecular level. Overall, very few trials have shown to be efficient, and safety concerns have emerged, as a result of several patients deaths. There is a need for new techniques able to improve both the knowledge of the therapeutic gene fate once administered and the early detection of events likely to lead to serious adverse events. In vivo imaging of a reporter gene associated with the therapeutic one is certainly the most promising technique for these goals. Among available imaging modalities, nuclear imaging is the most likely to be applied to patients. This review begins with a summary of current knowledge about the steps that a therapeutic gene has to cross from vector delivery to appropriate expression in target cells. We show how gene imaging could allow to investigate many pitfalls of trials by providing a better understanding of these steps in patients. The reporter genes available for nuclear imaging are presented in the second section, through animal studies. Then, relevant examples of clinical trials are presented. These include cancer (suicide gene therapy and adoptive immunotherapy), ischemic heart diseases and cystic fibrosis. The results are commented with emphasis on the role of nuclear imaging to address the questions raised by these studies, and imaging studies carried out on animals or patients for the corresponding diseases or organs are presented. The results obtained in animal studies warrant the introduction of gene imaging in clinical trials. (authors)

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.

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

Gene doping: gene delivery for olympic victory.

Science.gov (United States)

Gould, David

2013-08-01

With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. © 2012 The Author. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy.

Science.gov (United States)

Yang, Shuo; Ma, Si-Qi; Wan, Xing; He, Heng; Pei, Han; Zhao, Min-Jian; Chen, Chen; Wang, Dao-Wen; Dong, Xiao-Yan; Yuan, Jia-Jia; Li, Bin

2016-08-01

Leber's hereditary optic neuropathy (LHON) is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP), optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2-9) received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8) and untreated eyes (Patients 2, 3, 4, 6 and 8). Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1) who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains stable in the

Long-term outcomes of gene therapy for the treatment of Leber's hereditary optic neuropathy

Directory of Open Access Journals (Sweden)

Shuo Yang

2016-08-01

Full Text Available Leber's hereditary optic neuropathy (LHON is a disease that leads to blindness. Gene therapy has been investigated with some success, and could lead to important advancements in treating LHON. This was a prospective, open-label trial involving 9 LHON patients at Tongji Hospital, Wuhan, China, from August 2011 to December 2015. The purpose of this study was to evaluate the long-term outcomes of gene therapy for LHON. Nine LHON patients voluntarily received an intravitreal injection of rAAV2-ND4. Systemic examinations and visual function tests were performed during the 36-month follow-up period to determine the safety and efficacy of this gene therapy. Based on successful experiments in an animal model of LHON, 1 subject also received an rAAV2-ND4 injection in the second eye 12 months after gene therapy was administered in the first eye. Recovery of visual acuity was defined as the primary outcome of this study. Changes in the visual field, visual evoked potential (VEP, optical coherence tomography findings, liver and kidney function, and antibodies against AAV2 were defined as secondary endpoints. Eight patients (Patients 2–9 received unilateral gene therapy and visual function improvement was observed in both treated eyes (Patients 4, 6, 7, and 8 and untreated eyes (Patients 2, 3, 4, 6 and 8. Visual regression fluctuations, defined as changes in visual acuity greater than or equal to 0.3 logMAR, were observed in Patients 2 and 9. Age at disease onset, disease duration, and the amount of remaining optic nerve fibers did not have a significant effect on the visual function improvement. The visual field and pattern reversal VEP also improved. The patient (Patient 1 who received gene therapy in both eyes had improved visual acuity in the injected eye after the first treatment. Unfortunately, visual acuity in this eye decreased 3 months after he received gene therapy in the second eye. Animal experiments suggested that ND4 expression remains

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

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Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

Biomarkers in T cell therapy clinical trials

Directory of Open Access Journals (Sweden)

Kalos Michael

2011-08-01

Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.

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

Gene therapy a promising treatment for breast cancer: current scenario in pakistan

International Nuclear Information System (INIS)

Muzavir, S.R.; Zahra, S.A.; Ahmad, A.

2012-01-01

Breast cancer is one of the most common cancers among women around the world. It accounts for 22.9% of all the cancers and 18% of all female cancers in the world. One million new cases of breast cancer are diagnosed every year. Pakistan has more alarming situation with 90,000 new cases and ending up into 40,000 deaths annually. The risk factor for a female to develop breast cancer as compared with male is 100 : 1. The traditional way of treatment is by surgery, chemotherapy or radiotherapy. Advanced breast cancer is very difficult to treat with any of the traditional treatment options. A new treatment option in the form of gene therapy can be a promising treatment for breast cancer. Gene therapy provides treatment option in the form of targeting mutated gene, expression of cancer markers on the surface of cells, blocking the metastasis and induction of apoptosis, etc. Gene therapy showed very promising results for treatment of various cancers. All this is being trialed, experimented and practiced outside of Pakistan. Therefore, there is an immense need that this kind of work should be started in Pakistan. There are many good research institutes as well as well-reputed hospitals in Pakistan. Presently, there is a need to develop collaboration between research institutes and hospitals, so that the basic work and clinical trials can be done to treat breast cancer patients in the country. This collaboration will prove to be very healthy and will not only strength research institute but also will be very beneficial for cancer patients. (author)

Gene Therapy with Endogenous Inhibitors of Angiogenesis for Neovascular Age-Related Macular Degeneration: Beyond Anti-VEGF Therapy

Directory of Open Access Journals (Sweden)

Selwyn M. Prea

2015-01-01

Full Text Available Age-related macular degeneration (AMD is the leading cause of substantial and irreversible vision loss amongst elderly populations in industrialized countries. The advanced neovascular (or “wet” form of the disease is responsible for severe and aggressive loss of central vision. Current treatments aim to seal off leaky blood vessels via laser therapy or to suppress vessel leakage and neovascular growth through intraocular injections of antibodies that target vascular endothelial growth factor (VEGF. However, the long-term success of anti-VEGF therapy can be hampered by limitations such as low or variable efficacy, high frequency of administration (usually monthly, potentially serious side effects, and, most importantly, loss of efficacy with prolonged treatment. Gene transfer of endogenous antiangiogenic proteins is an alternative approach that has the potential to provide long-term suppression of neovascularization and/or excessive vascular leakage in the eye. Preclinical studies of gene transfer in a large animal model have provided impressive preliminary results with a number of transgenes. In addition, a clinical trial in patients suffering from advanced neovascular AMD has provided proof-of-concept for successful gene transfer. In this mini review, we summarize current theories pertaining to the application of gene therapy for neovascular AMD and the potential benefits when used in conjunction with endogenous antiangiogenic proteins.

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

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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.

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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.

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.

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

Mesenchymal stem cell-based gene therapy: A promising therapeutic strategy.

Science.gov (United States)

Mohammadian, Mozhdeh; Abasi, Elham; Akbarzadeh, Abolfazl

2016-08-01

Mesenchymal stem cells (MSCs) are multipotent stromal cells that exist in bone marrow, fat, and so many other tissues, and can differentiate into a variety of cell types including osteoblasts, chondrocytes, and adipocytes, as well as myocytes and neurons. Moreover, they have great capacity for self-renewal while maintaining their multipotency. Their capacity for proliferation and differentiation, in addition to their immunomodulatory activity, makes them very promising candidates for cell-based regenerative medicine. Moreover, MSCs have the ability of mobilization to the site of damage; therefore, they can automatically migrate to the site of injury via their chemokine receptors following intravenous transplantation. In this respect, they can be applied for MSC-based gene therapy. In this new therapeutic method, genes of interest are introduced into MSCs via viral and non-viral-based methods that lead to transgene expression in them. Although stem cell-based gene therapy is a relatively new strategy, it lights a new hope for the treatment of a variety of genetic disorders. In the near future, MSCs can be of use in a vast number of clinical applications, because of their uncomplicated isolation, culture, and genetic manipulation. However, full consideration is still crucial before they are utilized for clinical trials, because the number of studies that signify the advantageous effects of MSC-based gene therapy are still limited.

Potential mechanisms for cell-based gene therapy to treat HIV/AIDS.

Science.gov (United States)

Herrera-Carrillo, Elena; Berkhout, Ben

2015-02-01

An estimated 35 million people are infected with HIV worldwide. Anti-retroviral therapy (ART) has reduced the morbidity and mortality of HIV-infected patients but efficacy requires strict adherence and the treatment is not curative. Most importantly, the emergence of drug-resistant virus strains and drug toxicity can restrict the long-term therapeutic efficacy in some patients. Therefore, novel treatment strategies that permanently control or eliminate the virus and restore the damaged immune system are required. Gene therapy against HIV infection has been the topic of intense investigations for the last two decades because it can theoretically provide such a durable anti-HIV control. In this review we discuss two major gene therapy strategies to combat HIV. One approach aims to kill HIV-infected cells and the other is based on the protection of cells from HIV infection. We discuss the underlying molecular mechanisms for candidate approaches to permanently block HIV infection, including the latest strategies and future therapeutic applications. Hematopoietic stem cell-based gene therapy for HIV/AIDS may eventually become an alternative for standard ART and should ideally provide a functional cure in which the virus is durably controlled without medication. Recent results from preclinical research and early-stage clinical trials support the feasibility and safety of this novel strategy.

Clinical trial registration in physical therapy journals: a cross-sectional study.

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Babu, Abraham Samuel; Veluswamy, Sundar Kumar; Rao, Pratiksha Tilak; Maiya, Arun G

2014-01-01

Clinical trial registration has become an important part of editorial policies of various biomedical journals, including a few physical therapy journals. However, the extent to which editorial boards enforce the need for trial registration varies across journals. The purpose of this study was to identify editorial policies and reporting of trial registration details in MEDLINE-indexed English-language physical therapy journals. This study was carried out using a cross-sectional design. Editorial policies on trial registration of MEDLINE-indexed member journals of the International Society of Physiotherapy Journal Editors (ISPJE) (Journal of Geriatric Physical Therapy, Journal of Hand Therapy, Journal of Neurologic Physical Therapy, Journal of Orthopaedic and Sports Physical Therapy, Journal of Physiotherapy [formerly Australian Journal of Physiotherapy], Journal of Science and Medicine in Sport, Manual Therapy, Physical Therapy, Physical Therapy in Sport, Physiotherapy, Physiotherapy Research International, Physiotherapy Theory and Practice, and Revista Brasileira de Fisioterapia) were reviewed in April 2013. Full texts of reports of clinical trials published in these journals between January 1, 2008, and December 31, 2012, were independently assessed for information on trial registration. Among the 13 journals, 8 recommended trial registration, and 6 emphasized prospective trial registration. As of April 2013, 4,618 articles were published between January 2008 and December 2012, of which 9% (417) were clinical trials and 29% (121/417) of these reported trial registration details. A positive trend in reporting of trial registration was observed from 2008 to 2012. The study was limited to MEDLINE-indexed ISPJE member journals. Editorial policies on trial registration of physical therapy journals and a rising trend toward reporting of trial registration details indicate a positive momentum toward trial registration. Physical therapy journal editors need to show

Chelation therapy after the Trial to Assess Chelation Therapy: results of a unique trial

Science.gov (United States)

Avila, Maria D.; Escolar, Esteban; Lamas, Gervasio A.

2014-01-01

Purpose of review EDTA chelation therapy has been in off-label use for the treatment of atherosclerosis. We review the results of the first large-scale randomized trial of this treatment. Recent findings The trial to assess chelation therapy was a $30 million National Institutes of Health-funded study of the safety and efficacy of EDTA-based chelation infusions in 1708 post-myocardial infarction (MI) patients. The trial to assess chelation therapy demonstrated a significant (P = 0.035) 18% reduction in a combined primary endpoint of death, MI, stroke, coronary revascularization, or hospitalization for angina. In diabetic patients the benefit was more extreme, with a 41% relative reduction in risk (P = 0.0002) and a 43% reduction in total mortality (P = 0.011). Safety data were favorable. A reduction of oxidative stress by chelation of toxic metals has been proposed as a possible mechanism of action. Summary Recent research suggests that EDTA chelation may be a well-tolerated and effective treatment for post-MI patients. Future replication and mechanistic studies are important prior to implementation in all post-MI patients. PMID:25023079

Therapeutic misconception in early phase gene transfer trials.

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Henderson, Gail E; Easter, Michele M; Zimmer, Catherine; King, Nancy M P; Davis, Arlene M; Rothschild, Barbra Bluestone; Churchill, Larry R; Wilfond, Benjamin S; Nelson, Daniel K

2006-01-01

Many subjects in early phase clinical trials expect to benefit in some way from the research intervention. It is understandable that people hope for improvement in their condition, no matter what the evidence. Yet unreasonable expectation of medical benefit may reflect problems with informed consent: Investigators may not disclose clearly that direct medical benefit from an early phase experimental intervention is unlikely or impossible, or subjects may not appreciate the differences between treatment and research. This paper presents findings from recent interviews with researchers and subjects and analysis of consent forms in early phase gene transfer research, a cutting-edge technology often called 'gene therapy'. We use three variables to construct a composite measure of therapeutic misconception TM, tapping misconceptions about the purposes of early phase research and the potential for direct medical benefit in these trials. Our multivariate model demonstrates the importance of both subject- and study-level factors as predictors of this TM index: education, disease type, and communication by study personnel about the likelihood of benefit. We hope that this work will deepen the discussion of how to define and measure TM, and refine the specification of factors that are related to subjects' TM.

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

Historical and Clinical Experiences of Gene Therapy  for Solid Cancers in China

Directory of Open Access Journals (Sweden)

Bo Li

2017-02-01

Full Text Available Based on the theoretical and clinical development of modern medicines, gene therapy has been a promising treatment strategy for cancer and other diseases. The practice of gene therapy is nearly 27 years old, since the first authorized gene transfer study took place at the National Institute of Health in 1989. However, gene therapy was not readily adopted worldwide, until recently. Several gene therapy clinical trials have been carried out in China since 1998, and medical research in China has flourished. In this report, we review the history of gene therapy in China, focusing on treatment protocol, the administration cycle, dosage calculation, and the evaluation of therapeutic effects, in order to provide more information for the additional development of this promising treatment strategy.

Gene therapy: a lipofection approach for gene transfer into primary endothelial cells.

Science.gov (United States)

Young, A T L; Lakey, J R T; Murray, A G; Moore, R B

2002-01-01

Despite the great potential of gene therapy to become a new treatment modality in future medicine, there are still many limitations to overcome before this gene approach can pass to the stage of human trial. The foremost obstacle is the development of a safe, efficient, and efficacious vector system for in vivo gene application. This study evaluated the efficacy of lipofection as a gene delivery vehicle into primary endothelial cells. Transfection efficiency of several lipid-based reagents (Effectene, Fugene 6, DOTAP) was examined at experimental temperatures of 37 degrees C, 24 degrees C, and 6 degrees C. Human umbilical vein endothelial cells (HUVECs) were transfected with the enhanced green fluorescent protein (EGFP) using precise amounts of DNA (Effectene, 0.2 microg; Fugene 6, 0.5 microg; DOTAP, 2.5 microg) and lipids (Effectene, 10 microl; Fugene 6, 6 microl; DOTAP, 15 microl) optimized in our laboratory. Duration of incubation in the DNA/lipid transfection mixture varied for each lipid transfectant as follows: 5 h for both Fugene 6 and DOTAP and 3 h for Effectene. Efficiency of transfection was quantified by microscopic evaluation of EFGP expression in a minimum of 100 cells per group. Transfection efficiencies achieved with these lipofection agents were 34 +/- 1.3% (mean +/- SEM), 33 +/- 1.4%, and 18 +/- 1.5% for Effectene, Fugene 6, and DOTAP, respectively, at 37 degrees C. Transfection results were lower at 24 degrees C with mean efficiencies of 26 +/- 2.4% for Effectene, 14 +/- 2.9% for Fugene 6, and 15 +/- 3.2% for DOTAP. Furthermore, mean efficiencies at 6 degrees C were 6 +/- 0.5%, 8 +/- 1.5%, and 6 +/- 0.0% for Effectene, Fugene 6, and DOTAP, respectively. Efficiency of transfection appeared to be temperature dependent (ANOVA; p lipofection a potential gene delivery strategy for in vivo gene therapy.

From Molecular Biology to Clinical Trials: Toward Personalized Colorectal Cancer Therapy.

Science.gov (United States)

Palma, Sabina; Zwenger, Ariel O; Croce, María V; Abba, Martín C; Lacunza, Ezequiel

2016-06-01

During the past years, molecular studies through high-throughput technologies have led to the confirmation of critical alterations in colorectal cancer (CRC) and the discovery of some new ones, including mutations, DNA methylations, and structural chromosomal changes. These genomic alterations might act in concert to dysregulate specific signaling pathways that normally exert their functions on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Targeted therapy against key components of altered signaling pathways has allowed an improvement in CRC treatment. However, a significant percentage of patients with CRC and metastatic CRC will not benefit from these targeted therapies and will be restricted to systemic chemotherapy. Mechanisms of resistance have been associated with specific gene alterations. To fully understand the nature and significance of the genetic and epigenetic defects in CRC that might favor a tumor evading a given therapy, much work remains. Therefore, a dynamic link between basic molecular research and preclinical studies, which ultimately constitute the prelude to standardized therapies, is very important to provide better and more effective treatments against CRC. We present an updated revision of the main molecular features of CRC and their associated therapies currently under study in clinical trials. Moreover, we performed an unsupervised classification of CRC clinical trials with the aim of obtaining an overview of the future perspectives of preclinical studies. Copyright © 2015 Elsevier Inc. All rights reserved.

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.)

Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

Science.gov (United States)

Callan, Mary Beth; Haskins, Mark E; Wang, Ping; Zhou, Shangzhen; High, Katherine A; Arruda, Valder R

2016-01-01

Severe hemophilia A (HA) is an inherited bleeding disorder characterized by dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV) vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency) and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

Rational Autologous Cell Sources For Therapy of Heart Failure - Vehicles and Targets For Gene and RNA Therapies.

Science.gov (United States)

Lampinen, Milla; Vento, Antti; Laurikka, Jari; Nystedt, Johanna; Mervaala, Eero; Harjula, Ari; Kankuri, Esko

2016-01-01

This review focuses on the possibilities for intraoperative processing and isolation of autologous cells, particularly atrial appendage-derived cells (AADCs) and cellular micrografts, and their straightforward use in cell transplantation for heart failure therapy. We review the potential of autologous tissues to serve as sources for cell therapy and consider especially those tissues that are used in surgery but from which the excess is currently discarded as surgical waste. We compare the inculture expanded cells to the freshly isolated ones in terms of evidence-based cost-efficacy and their usability as gene- and RNA therapy vehicles. We also review how financial and authority-based decisions and restrictions sculpt the landscape for patients to participate in academic-based trials. Finally, we provide an insight example into AADCs isolation and processing for epicardial therapy during coronary artery bypass surgery.

Gene therapy in periodontics.

Science.gov (United States)

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.

Investor Outlook: Focus on Upcoming LCA2 Gene Therapy Phase III Results.

Science.gov (United States)

Schimmer, Joshua; Breazzano, Steven

2015-09-01

Investor interest in gene therapy has increased substantially over the past few years, and the next major catalyst for the field is likely to be Spark Therapeutics's phase III trial for the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders). Analysis of the approach from the basic genetics, underlying visual mechanisms, clinical data, and commercialization considerations helps frame investor expectations and the potential implications for the broader field.

Cancer suicide gene therapy: a patent review.

Science.gov (United States)

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.

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)

Core journals that publish clinical trials of physical therapy interventions.

Science.gov (United States)

Costa, Leonardo Oliveira Pena; Moseley, Anne M; Sherrington, Catherine; Maher, Christopher G; Herbert, Robert D; Elkins, Mark R

2010-11-01

The objective of this study was to identify core journals in physical therapy by identifying those that publish the most randomized controlled trials of physical therapy interventions, provide the highest-quality reports of randomized controlled trials, and have the highest journal impact factors. This study was an audit of a bibliographic database. All trials indexed in the Physiotherapy Evidence Database (PEDro) were analyzed. Journals that had published at least 80 trials were selected. The journals were ranked in 4 ways: number of trials published; mean total PEDro score of the trials published in the journal, regardless of publication year; mean total PEDro score of the trials published in the journal from 2000 to 2009; and 2008 journal impact factor. The top 5 core journals in physical therapy, ranked by the total number of trials published, were Archives of Physical Medicine and Rehabilitation, Clinical Rehabilitation, Spine, British Medical Journal (BMJ), and Chest. When the mean total PEDro score was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, Journal of the American Medical Association (JAMA), Stroke, Spine, and Clinical Rehabilitation. When the mean total PEDro score of the trials published from 2000 to 2009 was used as the ranking criterion, the top 5 journals were Journal of Physiotherapy, JAMA, Lancet, BMJ, and Pain. The most highly ranked physical therapy-specific journals were Physical Therapy (ranked eighth on the basis of the number of trials published) and Journal of Physiotherapy (ranked first on the basis of the quality of trials). Finally, when the 2008 impact factor was used for ranking, the top 5 journals were JAMA, Lancet, BMJ, American Journal of Respiratory and Critical Care Medicine, and Thorax. There were no significant relationships among the rankings on the basis of trial quality, number of trials, or journal impact factor. Physical therapists who are trying to keep up-to-date by reading the best

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

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

NCI-MATCH Trial Links Targeted Drugs to Mutations

Science.gov (United States)

Investigators for the nationwide trial, NCI-MATCH: Molecular Analysis for Therapy Choice, announced that the trial will seek to determine whether targeted therapies for people whose tumors have specific gene mutations will be effective regardless of their cancer type. NCI-MATCH will incorporate more than 20 different study drugs or drug combinations, each targeting a specific gene mutation, in order to match each patient in the trial with a therapy that targets a molecular abnormality in their tumor.

Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial.

Science.gov (United States)

Rakoczy, Elizabeth P; Lai, Chooi-May; Magno, Aaron L; Wikstrom, Matthew E; French, Martyn A; Pierce, Cora M; Schwartz, Steven D; Blumenkranz, Mark S; Chalberg, Thomas W; Degli-Esposti, Mariapia A; Constable, Ian J

2015-12-12

Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection. In this single-centre, phase 1, randomised controlled trial, we enrolled patients with wet age-related macular degeneration at the Lions Eye Institute and the Sir Charles Gairdner Hospital (Nedlands, WA, Australia). Eligible patients had to be aged 65 years or older, have age-related macular degeneration secondary to active subfoveal choroidal neovascularisation, with best corrected visual acuity (BCVA) of 3/60-6/24 and 6/60 or better in the other eye. Patients were randomly assigned (3:1) to receive either 1 × 10(10) vector genomes (vg; low-dose rAAV.sFLT-1 group) or 1 × 10(11) vg (high-dose rAAV.sFLT-1 group), or no gene-therapy treatment (control group). Randomisation was done by sequential group assignment. All patients and investigators were unmasked. Staff doing the assessments were masked to the study group at study visits. All patients received ranibizumab at baseline and week 4, and rescue treatment during follow-up based on prespecified criteria including BCVA measured on the Early Treatment Diabetic Retinopathy Study (EDTRS) scale, optical coherence tomography, and fluorescein angiography. The primary endpoint was ocular and systemic safety. This trial is registered with ClinicalTrials.gov, number NCT01494805. From Dec 16, 2011, to April 5, 2012, we enrolled nine patients of whom eight were randomly assigned to receive either intervention (three patients in the low-dose rAAV.sFLT-1 group and three patients in the high-dose rAAV.sFLT-1 group) or no treatment (two patients in the control group). Subretinal injection of r

“My whole life is ethics!” Ordinary ethics and gene therapy clinical trials

DEFF Research Database (Denmark)

Addison, Courtney; Lassen, Jesper

2017-01-01

acquire some control in difficult medical situations, and practitioners can attune their care to their patients’ needs. The human provenance of gene therapy practice, and the irreducible sociality of ethics, means that understanding the ethics of this medical field also requires understanding the everyday...

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

Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial

NARCIS (Netherlands)

Maclaren, R.E.; Groppe, M.; Barnard, A.R.; Cottriall, C.L.; Tolmachova, T.; Seymour, L.; Clark, K.; During, M.J.; Cremers, F.P.M.; Black, G.C.M.; Lotery, A.J.; Downes, S.M.; Webster, A.R.; Seabra, M.C.

2014-01-01

BACKGROUND: Choroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with

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.

Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.

Directory of Open Access Journals (Sweden)

Mary Beth Callan

Full Text Available Severe hemophilia A (HA is an inherited bleeding disorder characterized by <1% of residual factor VIII (FVIII clotting activity. The disease affects several mammals including dogs, and, like humans, is associated with high morbidity and mortality. In gene therapy using adeno-associated viral (AAV vectors, the canine model has been one of the best predictors of the therapeutic dose tested in clinical trials for hemophilia B (factor IX deficiency and other genetic diseases, such as congenital blindness. Here we report our experience with liver gene therapy with AAV-FVIII in two outbred, privately owned dogs with severe HA that resulted in sustained expression of 1-2% of normal FVIII levels and prevented 90% of expected bleeding episodes. A Thr62Met mutation in the F8 gene was identified in one dog. These data recapitulate the improvement of the disease phenotype in research animals, and in humans, with AAV liver gene therapy for hemophilia B. Our experience is a novel example of the benefits of a relevant preclinical canine model to facilitate both translational studies in humans and improved welfare of privately owned dogs.

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.

Integration Site and Clonal Expansion in Human Chronic Retroviral Infection and Gene Therapy

Science.gov (United States)

Niederer, Heather A.; Bangham, Charles R. M.

2014-01-01

Retroviral vectors have been successfully used therapeutically to restore expression of genes in a range of single-gene diseases, including several primary immunodeficiency disorders. Although clinical trials have shown remarkable results, there have also been a number of severe adverse events involving malignant outgrowth of a transformed clonal population. This clonal expansion is influenced by the integration site profile of the viral integrase, the transgene expressed, and the effect of the viral promoters on the neighbouring host genome. Infection with the pathogenic human retrovirus HTLV-1 also causes clonal expansion of cells containing an integrated HTLV-1 provirus. Although the majority of HTLV-1-infected people remain asymptomatic, up to 5% develop an aggressive T cell malignancy. In this review we discuss recent findings on the role of the genomic integration site in determining the clonality and the potential for malignant transformation of cells carrying integrated HTLV-1 or gene therapy vectors, and how these results have contributed to the understanding of HTLV-1 pathogenesis and to improvements in gene therapy vector safety. PMID:25365582

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.

TU-G-BRB-00: Clinical Trials in Proton and Particle Therapy

International Nuclear Information System (INIS)

2015-01-01

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. The lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial

Maternal uterine artery VEGF gene therapy for treatment of intrauterine growth restriction.

Science.gov (United States)

David, Anna L

2017-11-01

Intrauterine growth restriction (IUGR) is a serious pregnancy complication affecting approximately 8% of all pregnancies. The aetiology is believed to be insufficient maternal uteroplacental perfusion which prevents adequate nutrient and oxygen availability for the fetus. There is no treatment that can improve uteroplacental perfusion and thereby increase fetal growth in the uterus. Maternal uterine artery gene therapy presents a promising treatment strategy for IUGR, with the use of adenoviral vectors encoding for proteins such as Vascular Endothelial Growth Factor (VEGF) demonstrating improvements in fetal growth and neonatal outcome in preclinical studies. Mechanistically, maternal VEGF gene therapy delivered to the uterine arteries increases uterine blood flow and enhances vascular relaxation short term, while reducing vascular contractility long term. It also leads to vascular remodeling with increased endothelial cell proliferation in the perivascular adventitia of uterine arteries. Safety assessments suggest no vector spread to the fetus and no adverse risk to the mother or fetus; a clinical trial is in development. This article assesses research into VEGF maternal uterine artery directed gene therapy for IUGR, investigating the use of transgenes and vectors, their route of administration in obstetrics, and the steps that will be needed to take this treatment modality into the clinic. Copyright © 2017 Elsevier Ltd. All rights reserved.

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 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

Gene electrotransfer in clinical trials

DEFF Research Database (Denmark)

Gehl, Julie

2014-01-01

Electroporation is increasingly being used for delivery of chemotherapy to tumors. Likewise, gene delivery by electroporation is rapidly gaining momentum for both vaccination purposes and for delivery of genes coding for other therapeutic molecules, such as chronic diseases or cancer. This chapter...... describes how gene therapy may be performed using electric pulses to enhance uptake and expression....

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.

Oversight and management of a cell therapy clinical trial network: experience and lessons learned.

Science.gov (United States)

Moyé, Lemuel A; Sayre, Shelly L; Westbrook, Lynette; Jorgenson, Beth C; Handberg, Eileen; Anwaruddin, Saif; Wagner, Kristi A; Skarlatos, Sonia I

2011-09-01

The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This article describes the Network's challenges as it initiated three protocols in a polarized cultural atmosphere at a time when oversight bodies were positioning themselves for the tightest vigilance of promising new therapies. Effective strategies involving ongoing education, open communication, and relationship building with the oversight community are discussed. Copyright © 2011 Elsevier Inc. All rights reserved.

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

Directory of Open Access Journals (Sweden)

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

Directory of Open Access Journals (Sweden)

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.

Inducement of radionuclides targeting therapy by gene transfection

International Nuclear Information System (INIS)

Luo Quanyong

2001-01-01

The author presents an overview of gene transfection methods to genetically induce tumor cells to express enhanced levels of cell surface antigens and receptors to intake radiolabeled antibody and peptide targeting and thus increase their therapeutic effect in radiotherapy. The current research include inducement of radioimmunotherapy through CEA gene transfection, inducement of iodine-131 therapy by sodium iodide symporter gene transfection and inducement of MIBG therapy by noradrenaline transporter gene transfection. These studies raise the prospect that gene-therapy techniques could be used to enable the treatment of a wide range of tumors with radiopharmaceuticals of established clinical acceptability

High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies

Directory of Open Access Journals (Sweden)

Frank A Giordano

Full Text Available Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies, it is not useful for large-scale analyses. To explore whether vector integration site (IS recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification–mediated PCR (LAM-PCR or nonrestrictive LAM-PCR (nrLAM-PCR, both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM-PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand.

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

Lentiviral-Mediated Gene Therapy in Fanconi Anemia-A Mice Reveals Long-Term Engraftment and Continuous Turnover of Corrected HSCs.

Science.gov (United States)

Molina-Estevez, F Javier; Nowrouzi, Ali; Lozano, M Luz; Galy, Anne; Charrier, Sabine; von Kalle, Christof; Guenechea, Guillermo; Bueren, Juan A; Schmidt, Manfred

2015-01-01

Fanconi anemia is a DNA repair-deficiency syndrome mainly characterized by cancer predisposition and bone marrow failure. Trying to restore the hematopoietic function in these patients, lentiviral vector-mediated gene therapy trials have recently been proposed. However, because no insertional oncogenesis studies have been conducted so far in DNA repair-deficiency syndromes such as Fanconi anemia, we have carried out a genome-wide screening of lentiviral insertion sites after the gene correction of Fanca(-/-) hematopoietic stem cells (HSCs), using LAM-PCR and 454-pyrosequencing. Our studies first demonstrated that transduction of Fanca(-/-) HSCs with a lentiviral vector designed for clinical application efficiently corrects the phenotype of Fanconi anemia repopulating cells without any sign of toxicity. The identification of more than 6,500 insertion sites in primary and secondary recipients showed a polyclonal pattern of reconstitution, as well as a continuous turnover of corrected Fanca(-/-) HSC clones, without evidences of selection towards specific common integration sites. Taken together our data show, for the first time in a DNA repair-deficiency syndrome, that lentiviral vector-mediated gene therapy efficiently corrects the phenotype of affected HSCs and promotes a healthy pattern of clonal turnover in vivo. These studies will have a particular impact in the development of new gene therapy trials in patients affected by DNA repair syndromes, particularly in Fanconi anemia.

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.

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

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.

Imaging and Data Acquisition in Clinical Trials for Radiation Therapy

Energy Technology Data Exchange (ETDEWEB)

FitzGerald, Thomas J., E-mail: Thomas.Fitzgerald@umassmed.edu [Imaging and Radiation Oncology Core Rhode Island, University of Massachusetts Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts (United States); Bishop-Jodoin, Maryann [Imaging and Radiation Oncology Core Rhode Island, University of Massachusetts Medical School, Worcester, Massachusetts (United States); Followill, David S. [Imaging and Radiation Oncology Core Houston, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Galvin, James [Imaging and Radiation Oncology Core Philadelphia, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Knopp, Michael V. [Imaging and Radiation Oncology Core Ohio, Wexner Medical Center, Ohio State University, Columbus, Ohio (United States); Michalski, Jeff M. [Imaging and Radiation Oncology Core St. Louis, Washington University School of Medicine, St. Louis, Missouri (United States); Rosen, Mark A. [Imaging and Radiation Oncology Core Philadelphia, University of Pennsylvania Health System, Philadelphia, Pennsylvania (United States); Bradley, Jeffrey D. [Washington University School of Medicine–Radiation Oncology, St. Louis, Missouri (United States); Shankar, Lalitha K. [National Cancer Institute, Clinical Radiation Oncology Branch, Rockville, Maryland (United States); Laurie, Fran [Imaging and Radiation Oncology Core Rhode Island, University of Massachusetts Medical School, Worcester, Massachusetts (United States); Cicchetti, M. Giulia; Moni, Janaki [Imaging and Radiation Oncology Core Rhode Island, University of Massachusetts Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts (United States); Coleman, C. Norman; Deye, James A.; Capala, Jacek; Vikram, Bhadrasain [National Cancer Institute, Clinical Radiation Oncology Branch, Rockville, Maryland (United States)

2016-02-01

Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials.

Imaging and Data Acquisition in Clinical Trials for Radiation Therapy

International Nuclear Information System (INIS)

FitzGerald, Thomas J.; Bishop-Jodoin, Maryann; Followill, David S.; Galvin, James; Knopp, Michael V.; Michalski, Jeff M.; Rosen, Mark A.; Bradley, Jeffrey D.; Shankar, Lalitha K.; Laurie, Fran; Cicchetti, M. Giulia; Moni, Janaki; Coleman, C. Norman; Deye, James A.; Capala, Jacek; Vikram, Bhadrasain

2016-01-01

Cancer treatment evolves through oncology clinical trials. Cancer trials are multimodal and complex. Assuring high-quality data are available to answer not only study objectives but also questions not anticipated at study initiation is the role of quality assurance. The National Cancer Institute reorganized its cancer clinical trials program in 2014. The National Clinical Trials Network (NCTN) was formed and within it was established a Diagnostic Imaging and Radiation Therapy Quality Assurance Organization. This organization is Imaging and Radiation Oncology Core, the Imaging and Radiation Oncology Core Group, consisting of 6 quality assurance centers that provide imaging and radiation therapy quality assurance for the NCTN. Sophisticated imaging is used for cancer diagnosis, treatment, and management as well as for image-driven technologies to plan and execute radiation treatment. Integration of imaging and radiation oncology data acquisition, review, management, and archive strategies are essential for trial compliance and future research. Lessons learned from previous trials are and provide evidence to support diagnostic imaging and radiation therapy data acquisition in NCTN trials.

Gene Therapy for the Retinal Degeneration of Usher Syndrome Caused by Mutations in MYO7A.

Science.gov (United States)

Lopes, Vanda S; Williams, David S

2015-01-20

Usher syndrome is a deaf-blindness disorder. One of the subtypes, Usher 1B, is caused by loss of function of the gene encoding the unconventional myosin, MYO7A. A variety of different viral-based delivery approaches have been tested for retinal gene therapy to prevent the blindness of Usher 1B, and a clinical trial based on one of these approaches has begun. This review evaluates the different approaches. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

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...

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.

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.

Regulatory Oversight of Cell and Gene Therapy Products in Canada.

Science.gov (United States)

Ridgway, Anthony; Agbanyo, Francisca; Wang, Jian; Rosu-Myles, Michael

2015-01-01

Health Canada regulates gene therapy products and many cell therapy products as biological drugs under the Canadian Food and Drugs Act and its attendant regulations. Cellular products that meet certain criteria, including minimal manipulation and homologous use, may be subjected to a standards-based approach under the Safety of Human Cells, Tissues and Organs for Transplantation Regulations. The manufacture and clinical testing of cell and gene therapy products (CGTPs) presents many challenges beyond those for protein biologics. Cells cannot be subjected to pathogen removal or inactivation procedures and must frequently be administered shortly after final formulation. Viral vector design and manufacturing control are critically important to overall product quality and linked to safety and efficacy in patients through concerns such as replication competence, vector integration, and vector shedding. In addition, for many CGTPs, the value of nonclinical studies is largely limited to providing proof of concept, and the first meaningful data relating to appropriate dosing, safety parameters, and validity of surrogate or true determinants of efficacy must come from carefully designed clinical trials in patients. Addressing these numerous challenges requires application of various risk mitigation strategies and meeting regulatory expectations specifically adapted to the product types. Regulatory cooperation and harmonisation at an international level are essential for progress in the development and commercialisation of these products. However, particularly in the area of cell therapy, new regulatory paradigms may be needed to harness the benefits of clinical progress in situations where the resources and motivation to pursue a typical drug product approval pathway may be lacking.

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 adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.

Science.gov (United States)

Candotti, Fabio; Shaw, Kit L; Muul, Linda; Carbonaro, Denise; Sokolic, Robert; Choi, Christopher; Schurman, Shepherd H; Garabedian, Elizabeth; Kesserwan, Chimene; Jagadeesh, G Jayashree; Fu, Pei-Yu; Gschweng, Eric; Cooper, Aaron; Tisdale, John F; Weinberg, Kenneth I; Crooks, Gay M; Kapoor, Neena; Shah, Ami; Abdel-Azim, Hisham; Yu, Xiao-Jin; Smogorzewska, Monika; Wayne, Alan S; Rosenblatt, Howard M; Davis, Carla M; Hanson, Celine; Rishi, Radha G; Wang, Xiaoyan; Gjertson, David; Yang, Otto O; Balamurugan, Arumugam; Bauer, Gerhard; Ireland, Joanna A; Engel, Barbara C; Podsakoff, Gregory M; Hershfield, Michael S; Blaese, R Michael; Parkman, Robertson; Kohn, Donald B

2012-11-01

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.

Gene therapy for adenosine deaminase–deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans

Science.gov (United States)

Candotti, Fabio; Shaw, Kit L.; Muul, Linda; Carbonaro, Denise; Sokolic, Robert; Choi, Christopher; Schurman, Shepherd H.; Garabedian, Elizabeth; Kesserwan, Chimene; Jagadeesh, G. Jayashree; Fu, Pei-Yu; Gschweng, Eric; Cooper, Aaron; Tisdale, John F.; Weinberg, Kenneth I.; Crooks, Gay M.; Kapoor, Neena; Shah, Ami; Abdel-Azim, Hisham; Yu, Xiao-Jin; Smogorzewska, Monika; Wayne, Alan S.; Rosenblatt, Howard M.; Davis, Carla M.; Hanson, Celine; Rishi, Radha G.; Wang, Xiaoyan; Gjertson, David; Yang, Otto O.; Balamurugan, Arumugam; Bauer, Gerhard; Ireland, Joanna A.; Engel, Barbara C.; Podsakoff, Gregory M.; Hershfield, Michael S.; Blaese, R. Michael; Parkman, Robertson

2012-01-01

We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)–deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m2). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency. PMID:22968453

Gene Therapy and its applications in Dentistry

Directory of Open Access Journals (Sweden)

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.

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

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

Science.gov (United States)

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.

Gene therapy for carcinoma of the breast: Genetic ablation strategies

International Nuclear Information System (INIS)

Curiel, David T

2000-01-01

The gene therapy strategy of mutation compensation is designed to rectify the molecular lesions that are etiologic for neoplastic transformation. For dominant oncogenes, such approaches involve the functional knockout of the dysregulated cellular control pathways provoked by the overexpressed oncoprotein. On this basis, molecular interventions may be targeted to the transcriptional level of expression, via antisense or ribozymes, or post-transcriptionally, via intracellular single chain antibodies (intrabodies). For carcinoma of the breast, these approaches have been applied in the context of the disease linked oncogenes erbB-2 and cyclin D 1 , as well as the estrogen receptor. Neoplastic revision accomplished in modal systems has rationalized human trials on this basis

Exercise therapy, manual therapy, or both, for osteoarthritis of the hip or knee: a factorial randomised controlled trial protocol

Directory of Open Access Journals (Sweden)

Baxter G David

2009-02-01

Full Text Available Abstract Background Non-pharmacological, non-surgical interventions are recommended as the first line of treatment for osteoarthritis (OA of the hip and knee. There is evidence that exercise therapy is effective for reducing pain and improving function in patients with knee OA, some evidence that exercise therapy is effective for hip OA, and early indications that manual therapy may be efficacious for hip and knee OA. There is little evidence as to which approach is more effective, if benefits endure, or if providing these therapies is cost-effective for the management of this disorder. The MOA Trial (Management of OsteoArthritis aims to test the effectiveness of two physiotherapy interventions for improving disability and pain in adults with hip or knee OA in New Zealand. Specifically, our primary objectives are to investigate whether: 1. Exercise therapy versus no exercise therapy improves disability at 12 months; 2. Manual physiotherapy versus no manual therapy improves disability at 12 months; 3. Providing physiotherapy programmes in addition to usual care is more cost-effective than usual care alone in the management of osteoarthritis at 24 months. Methods This is a 2 × 2 factorial randomised controlled trial. We plan to recruit 224 participants with hip or knee OA. Eligible participants will be randomly allocated to receive either: (a a supervised multi-modal exercise therapy programme; (b an individualised manual therapy programme; (c both exercise therapy and manual therapy; or, (d no trial physiotherapy. All participants will continue to receive usual medical care. The outcome assessors, orthopaedic surgeons, general medical practitioners, and statistician will be blind to group allocation until the statistical analysis is completed. The trial is funded by Health Research Council of New Zealand Project Grants (Project numbers 07/199, 07/200. Discussion The MOA Trial will be the first to investigate the effectiveness and cost

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.

Gene therapy for CNS diseases – Krabbe disease

Directory of Open Access Journals (Sweden)

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.

Dual monitoring using 124I-FIAU and bioluminescence for HSV1-tk suicide gene therapy

International Nuclear Information System (INIS)

Lee, T. S.; Kim, J. H.; Kwon, H. C.

2007-01-01

Herpes simplex virus type I thymidine kinase (HSV-tk) is the most common reporter gene and is used in cancer gene therapy with a prodrug nucleoside analog, ganciclovir (GCV). The aim of this study is to evaluate therapeutic efficacy of suicide gene therapy with 2'-fluoro-2'-deoxy-1-D-arabinofuranosyl-5-[ 124 I] iodouracil ( 124 I - FIAU) and bioluminescence in retrovirally HSV -tk and firefly luciferase transduced hepatoma model. The HSV -tk and firefly luciferase (Luc) was retrovirally transduced and expressed in MCA rat Morris hepatoma cells. Nude mice with subcutaneous tumors, MCA and MCA-TK-Luc, were subjected to GCV treatment (50mg/Kg/d intraperitoneally) for 5 day. PET imaging and biodistribution with ( 124 I-FIAU) were performed at before and after initiation of therapy with GCV. Bioluminescent signal was also measured during GCV treatment. Before GCV treatment, no significant difference in tumor volume was found in tumors between MCA and MCA-TK-Luc. After GCV treatment, tumor volume of MCA-TK-Luc markedly reduced compared to that of MCA. In biodistribution study, 124 I-FIAU uptake after GCV therapy significantly decreased compared with pretreatment levels (34.8 13.67 %ID/g vs 7.6 2.59 %ID/g) and bioluminescent signal was also significantly decreased compared with pretreatment levels. In small animal PET imaging, 124 I-FIAU selectively localized in HSV -tk expressing tumor and the therapeutic efficacy of GCV treatment was evaluated by 124 I-FIAU PET imaging. 124 I-FIAU PET and bioluminescence imaging in HSV-tk suicide gene therapy were effective to evaluate the therapeutic response. 124 I-FIAU may serve as an efficient and selective agent for monitoring of transduced HSV1-tk gene expression in vivo in clinical trials

Regulation of Clinical Trials with Advanced Therapy Medicinal Products in Germany.

Science.gov (United States)

Renner, Matthias; Anliker, Brigitte; Sanzenbacher, Ralf; Schuele, Silke

2015-01-01

In the European Union, clinical trials for Advanced Therapy Medicinal Products are regulated at the national level, in contrast to the situation for a Marketing Authorisation Application, in which a centralised procedure is foreseen for these medicinal products. Although based on a common understanding regarding the regulatory requirement to be fulfilled before conduct of a clinical trial with an Advanced Therapy Investigational Medicinal Product, the procedures and partly the scientific requirements for approval of a clinical trial application differ between the European Union Member States. This chapter will thus give an overview about the path to be followed for a clinical trial application and the subsequent approval process for an Advanced Therapy Investigational Medicinal Product in Germany and will describe the role of the stakeholders that are involved. In addition, important aspects of manufacturing, quality control and non-clinical testing of Advanced Therapy Medicinal Products in the clinical development phase are discussed. Finally, current and future approaches for harmonisation of clinical trial authorisation between European Union Member States are summarised.

INGN 201: Ad-p53, Ad5CMV-p53, Adenoviral p53, INGN 101, p53 gene therapy--Introgen, RPR/INGN 201.

Science.gov (United States)

2003-01-01

Introgen's adenoviral p53 gene therapy [INGN 201, ADVEXIN] is in clinical development for the treatment of various cancers. The p53 tumour suppressor gene is deleted or mutated in many tumour cells and is one of the most frequently mutated genes in human tumours. INGN 201 has been shown to kill cancer cells directly. In August 2002, Introgen announced plans to file an application for INGN 201 with the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of head and neck cancer; the European filing will be submitted simultaneously with the previously scheduled (planned for 2004) submission of a Biologics License Application (BLA) for ADVEXIN to the US FDA. On 20 February 2003, INGN 201 received orphan drug designation from the US FDA for head and neck cancer. INGN 201 is available for licensing although Introgen favours retaining partial or full rights to the therapy in the US. Introgen Therapeutics and its collaborative partner for the p53 programme, Aventis Gencell, have been developing p53 gene therapy products. The agreement was originally signed by Rhône-Poulenc Rorer's Gencell division, which became Aventis Gencell after Rhône-Poulenc Rorer merged with Hoechst Marion Roussel to form Aventis Pharma. According to the original agreement, Introgen was responsible for phase I and preclinical development in North America, while Aventis Gencell was responsible for clinical trials conducted in Europe and for clinical trials in North America beyond phase I. In April 2001, Aventis Gencell and Introgen restructured their existing collaboration agreement for p53 gene therapy products. Aventis Gencell indicated that p53 research had suffered from internal competition for resources and was pulling back from its development agreement with Introgen for p53 gene therapy products. Introgen will assume responsibility for worldwide development of all p53 programmes and will obtain exclusive worldwide commercial rights to p53-based gene therapy

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.

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: 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.

Randomized Controlled Trials in Music Therapy: Guidelines for Design and Implementation.

Science.gov (United States)

Bradt, Joke

2012-01-01

Evidence from randomized controlled trials (RCTs) plays a powerful role in today's healthcare industry. At the same time, it is important that multiple types of evidence contribute to music therapy's knowledge base and that the dialogue of clinical effectiveness in music therapy is not dominated by the biomedical hierarchical model of evidence-based practice. Whether or not one agrees with the hierarchical model of evidence in the current healthcare climate, RCTs can contribute important knowledge to our field. Therefore, it is important that music therapists are prepared to design trials that meet current methodological standards and, equally important, are able to respond appropriately to those design aspects that may not be feasible in music therapy research. To provide practical guidelines to music therapy researchers for the design and implementation of RCTs as well as to enable music therapists to be well-informed consumers of RCT evidence. This article reviews key design aspects of RCTs and discusses how to best implement these standards in music therapy trials. A systematic presentation of basic randomization methods, allocation concealment strategies, issues related to blinding in music therapy trials and strategies for implementation, the use of treatment manuals, types of control groups, outcome selection, and sample size computation is provided. Despite the challenges of meeting all key design demands typical of an RCT, it is possible to design rigorous music therapy RCTs that accurately estimate music therapy treatment benefits.

Preparations for the next generation of clinical trials with proton therapy

International Nuclear Information System (INIS)

Newhauser, W.D.; Smith, A.R.; Fitzek, M.; Ibbott, G.; Munzenrider, J.

2002-01-01

Full text: As proton radiation therapy centers become more widely available, we anticipate an increase in clinical proton therapy research, e.g. clinical trials to compare the efficacy of proton therapy with that of conformal photon therapy. In this presentation, we explore some of the quality assurance (QA) work that will be necessary to support multi-institution clinical trials to include facilities in Europe, Asia and the United States. Specifically, we shall concentrate on three areas pertaining to practical clinical proton dosimetry for which clear, concise, and coherent guidance is needed. First, the existing proton therapy dosimetry protocols (e.g. ICRU Report 59, IAEA TRS-398) provide general methods that are well suited for adoption in proton therapy. Many additional techniques are required in order to implement dosimetry in a contemporary proton clinic. For example, special situations arise for small fields including those for radiosurgery and ocular treatments, and for rotational therapy. Fortunately, this additional information is emerging from various proton therapy centers. For example, Vatnitsky et al. described the dosimetry of small beams, Newhauser et al. described absolute proton dosimetry techniques for radiosurgery and for ocular beams. Newhauser et al. also reported on a general formalism and practical methods for dosimetry measurements in a rotational proton gantry. Our aim is to discuss some specific needs for the standardization of these tasks, which will be essential in achieving adequate uniformity in multi-institution clinical trials. Second, we will discuss means to standardize of writing the physics QA portion of protocols for multi-institution clinical trials, through which a statistically significant number of patient outcomes may be obtained more rapidly. Surprisingly, only two multi-institution proton clinical trials have been undertaken (a skull base sarcoma trial and a prostate cancer trial, both shared between MGH and Loma Linda

[Clinical Tests Testing New Therapies for Stargardt Disease].

Science.gov (United States)

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

2016-02-01

To provide information on currently ongoing clinical trials for Stargardt disease. We have searched the clinical trial register (www.clinicaltrials.gov) for the keyword "Stargardt" and list active ongoing studies. There are currently eight registered clinical trials enrolling patients with Stargardt disease; all in phase I or II aiming at four mechanisms of action: inhibition of the production of vitamin A toxic dimers, gene therapy restoring wild type transcription of the ABCA4 gene, neuroprotection preventing retinal cells from oxidative damage, and replacement of the damaged retinal pigment epithelium using stem cell therapy. The basic prerequisite for enrolment in the vast majority of clinical trials is confirmation of the clinical diagnosis by mutational analysis. The wide variety of therapies that are registered as clinical trials for Stargardt disease significantly raises the possibility that effective treatments will be available in the near future for this currently incurable condition and that molecular genetic testing should be increasingly considered. Stargardt disease, clinical trial, ABCA4, mutation.

Advanced therapy medicinal products: current and future perspectives.

Science.gov (United States)

Hanna, Eve; Rémuzat, Cécile; Auquier, Pascal; Toumi, Mondher

2016-01-01

Advanced therapy medicinal products (ATMPs) are innovative therapies that encompass gene therapy, somatic cell therapy, and tissue-engineered products. These therapies are expected to bring important health benefits, but also to substantially impact the pharmaceuticals budget. The aim of this study was to characterise the ATMPs in development and discuss future implications in terms of market access. Clinical trials were searched in the following databases: EudraCT (EU Drug Regulating Authorities Clinical Trials), ClinicalTrials.gov, and ICTRP (International Clinical Trials Registry Platform of the World Health Organization). Trials were classified by category of ATMP as defined by European regulation EC No. 1394/2007, as well as by development phase and disease area. The database search identified 939 clinical trials investigating ATMPs (85% ongoing, 15% completed). The majority of trials were in the early stages (Phase I, I/II: 64.3%, Phase II, II/III: 27.9%, Phase 3: 6.9%). Per category of ATMP, we identified 53.6% of trials for somatic cell therapies, 22.8% for tissue-engineered products, 22.4% for gene therapies, and 1.2% for combined products (incorporating a medical device). Disease areas included cancer (24.8%), cardiovascular diseases (19.4%), musculoskeletal (10.5%), immune system and inflammation (11.5%), neurology (9.1%), and others. Of the trials, 47.2% enrolled fewer than 25 patients. Due to the complexity and specificity of ATMPs, new clinical trial methodologies are being considered (e.g., small sample size, non-randomised trials, single-arm trials, surrogate endpoints, integrated protocols, and adaptive designs). Evidence generation post-launch will become unavoidable to address payers' expectations. ATMPs represent a fast-growing field of interest. Although most of the products are in an early development phase, the combined trial phase and the potential to cure severe chronic conditions suggest that ATMPs may reach the market earlier than

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.

Dual monitoring using {sup 124}I-FIAU and bioluminescence for HSV1-tk suicide gene therapy

Energy Technology Data Exchange (ETDEWEB)

Lee, T. S.; Kim, J. H.; Kwon, H. C. [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)] (and others)

2007-07-01

Herpes simplex virus type I thymidine kinase (HSV-tk) is the most common reporter gene and is used in cancer gene therapy with a prodrug nucleoside analog, ganciclovir (GCV). The aim of this study is to evaluate therapeutic efficacy of suicide gene therapy with 2'-fluoro-2'-deoxy-1-D-arabinofuranosyl-5-[{sup 124}I] iodouracil ({sup 124}I - FIAU) and bioluminescence in retrovirally HSV -tk and firefly luciferase transduced hepatoma model. The HSV -tk and firefly luciferase (Luc) was retrovirally transduced and expressed in MCA rat Morris hepatoma cells. Nude mice with subcutaneous tumors, MCA and MCA-TK-Luc, were subjected to GCV treatment (50mg/Kg/d intraperitoneally) for 5 day. PET imaging and biodistribution with ({sup 124}I-FIAU) were performed at before and after initiation of therapy with GCV. Bioluminescent signal was also measured during GCV treatment. Before GCV treatment, no significant difference in tumor volume was found in tumors between MCA and MCA-TK-Luc. After GCV treatment, tumor volume of MCA-TK-Luc markedly reduced compared to that of MCA. In biodistribution study, {sup 124}I-FIAU uptake after GCV therapy significantly decreased compared with pretreatment levels (34.8 13.67 %ID/g vs 7.6 2.59 %ID/g) and bioluminescent signal was also significantly decreased compared with pretreatment levels. In small animal PET imaging, {sup 124}I-FIAU selectively localized in HSV -tk expressing tumor and the therapeutic efficacy of GCV treatment was evaluated by {sup 124}I-FIAU PET imaging. {sup 124}I-FIAU PET and bioluminescence imaging in HSV-tk suicide gene therapy were effective to evaluate the therapeutic response. {sup 124}I-FIAU may serve as an efficient and selective agent for monitoring of transduced HSV1-tk gene expression in vivo in clinical trials.

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.

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.

Efficient Ex Vivo Engineering and Expansion of Highly Purified Human Hematopoietic Stem and Progenitor Cell Populations for Gene Therapy.

Science.gov (United States)

Zonari, Erika; Desantis, Giacomo; Petrillo, Carolina; Boccalatte, Francesco E; Lidonnici, Maria Rosa; Kajaste-Rudnitski, Anna; Aiuti, Alessandro; Ferrari, Giuliana; Naldini, Luigi; Gentner, Bernhard

2017-04-11

Ex vivo gene therapy based on CD34 + hematopoietic stem cells (HSCs) has shown promising results in clinical trials, but genetic engineering to high levels and in large scale remains challenging. We devised a sorting strategy that captures more than 90% of HSC activity in less than 10% of mobilized peripheral blood (mPB) CD34 + cells, and modeled a transplantation protocol based on highly purified, genetically engineered HSCs co-infused with uncultured progenitor cells. Prostaglandin E 2 stimulation allowed near-complete transduction of HSCs with lentiviral vectors during a culture time of less than 38 hr, mitigating the negative impact of standard culture on progenitor cell function. Exploiting the pyrimidoindole derivative UM171, we show that transduced mPB CD34 + CD38 - cells with repopulating potential could be expanded ex vivo. Implementing these findings in clinical gene therapy protocols will improve the efficacy, safety, and sustainability of gene therapy and generate new opportunities in the field of gene editing. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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)

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.

Clinical Trials

Medline Plus

Full Text Available ... as gene therapy) or vulnerable patients (such as children). A DSMB's role is to review data from a clinical trial for safety problems or differences in results among different groups. The DSMB also reviews research results ...

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 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

Lipidomic Evaluation of Feline Neurologic Disease after AAV Gene Therapy

Directory of Open Access Journals (Sweden)

Heather L. Gray-Edwards

2017-09-01

Full Text Available GM1 gangliosidosis is a fatal lysosomal disorder, for which there is no effective treatment. Adeno-associated virus (AAV gene therapy in GM1 cats has resulted in a greater than 6-fold increase in lifespan, with many cats remaining alive at >5.7 years of age, with minimal clinical signs. Glycolipids are the principal storage product in GM1 gangliosidosis whose pathogenic mechanism is not completely understood. Targeted lipidomics analysis was performed to better define disease mechanisms and identify markers of disease progression for upcoming clinical trials in humans. 36 sphingolipids and subspecies associated with ganglioside biosynthesis were tested in the cerebrospinal fluid of untreated GM1 cats at a humane endpoint (∼8 months, AAV-treated GM1 cats (∼5 years old, and normal adult controls. In untreated GM1 cats, significant alterations were noted in 16 sphingolipid species, including gangliosides (GM1 and GM3, lactosylceramides, ceramides, sphingomyelins, monohexosylceramides, and sulfatides. Variable degrees of correction in many lipid metabolites reflected the efficacy of AAV gene therapy. Sphingolipid levels were highly predictive of neurologic disease progression, with 11 metabolites having a coefficient of determination (R2 > 0.75. Also, a specific detergent additive significantly increased the recovery of certain lipid species in cerebrospinal fluid samples. This report demonstrates the methodology and utility of targeted lipidomics to examine the pathophysiology of lipid storage disorders.

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

Comparison of manual therapy and exercise therapy in osteoarthritis of the hip: a randomized clinical trial.

NARCIS (Netherlands)

Hoeksma, H.L.; Dekker, J.; Ronday, H.K.; Heering, A.; Lubbe, N. van der; Vel, C.; Breedveld, F.C.; Ende, C.H.M. van den

2004-01-01

OBJECTIVE: To determine the effectiveness of a manual therapy program compared with an exercise therapy program in patients with osteoarthritis (OA) of the hip. METHODS: A single-blind, randomized clinical trial of 109 hip OA patients was carried out in the outpatient clinic for physical therapy of

Enhanced combined tumor-specific oncolysis and suicide gene therapy for prostate cancer using M6 promoter.

Science.gov (United States)

Ahn, M; Lee, S-J; Li, X; Jiménez, J A; Zhang, Y-P; Bae, K-H; Mohammadi, Y; Kao, C; Gardner, T A

2009-01-01

Enzyme pro-drug suicide gene therapy has been hindered by inefficient viral delivery and gene transduction. To further explore the potential of this approach, we have developed AdIU1, a prostate-restricted replicative adenovirus (PRRA) armed with the herpes simplex virus thymidine kinase (HSV-TK). In our previous Ad-OC-TK/ACV phase I clinical trial, we demonstrated safety and proof of principle with a tissue-specific promoter-based TK/pro-drug therapy using a replication-defective adenovirus for the treatment of prostate cancer metastases. In this study, we aimed to inhibit the growth of androgen-independent (AI), PSA/PSMA-positive prostate cancer cells by AdIU1. In vitro the viability of an AI- PSA/PSMA-expressing prostate cancer cell line, CWR22rv, was significantly inhibited by treatment with AdIU1 plus GCV (10 microg ml(-1)), compared with AdIU1 treatment alone and also cytotoxicity was observed following treatment with AdIU1 plus GCV only in PSA/PSMA-positive CWR22rv and C4-2 cells, but not in the PSA/PSMA-negative cell line, DU-145. In vivo assessment of AdIU1 plus GCV treatment revealed a stronger therapeutic effect against CWR22rv tumors in nude mice than treatment with AdIU1 alone, AdE4PSESE1a alone or in combination with GCV. Our results demonstrate the therapeutic potential of specific-oncolysis and suicide gene therapy for AI-PSA/PSMA-positive prostate cancer gene therapy.

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

Fetal gene therapy: recent advances and current challenges.

Science.gov (United States)

Mattar, Citra N; Choolani, Mahesh; Biswas, Arijit; Waddington, Simon N; Chan, Jerry K Y

2011-10-01

Fetal gene therapy (FGT) can potentially be applied to perinatally lethal monogenic diseases for rescuing clinically severe phenotypes, increasing the probability of intact neurological and other key functions at birth, or inducing immune tolerance to a transgenic protein to facilitate readministration of the vector/protein postnatally. As the field is still at an experimental stage, there are several important considerations regarding the practicality and the ethics of FGT. Here, through a review of FGT studies, the authors discuss the role and applications of FGT, the progress made with animal models that simulate human development, possible adverse effects in the recipient fetus and the mother and factors that affect clinical translation. Although there are valid safety and ethical concerns, the authors argue that there may soon be enough convincing evidence from non-human primate models to take the next step towards clinical trials in the near future. © 2011 Informa UK, Ltd.

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...

Art Therapy and Cognitive Processing Therapy for Combat-Related PTSD: A Randomized Controlled Trial

Science.gov (United States)

Campbell, Melissa; Decker, Kathleen P.; Kruk, Kerry; Deaver, Sarah P.

2016-01-01

This randomized controlled trial was designed to determine if art therapy in conjunction with Cognitive Processing Therapy (CPT) was more effective for reducing symptoms of combat posttraumatic stress disorder (PTSD) than CPT alone. Veterans (N = 11) were randomized to receive either individual CPT, or individual CPT in conjunction with individual…

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.

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

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.

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.

Communicating in context: a priority for gene therapy researchers.

Science.gov (United States)

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.

Gene therapies that restore dystrophin expression for the treatment of Duchenne muscular dystrophy

Science.gov (United States)

Robinson-Hamm, Jacqueline N.; Gersbach, Charles A.

2016-01-01

Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength. Exon skipping with oligonucleotides has been successful in several animal models and evaluated in multiple clinical trials. Next-generation oligonucleotide formulations offer significant promise to build on these results. All these approaches to restoring dystrophin expression are encouraging, but many hurdles remain. This review summarizes the current state of these technologies and summarizes considerations for their future development. PMID:27542949

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

Directory of Open Access Journals (Sweden)

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

‘Third wave’ cognitive therapy versus mentalization-based therapy for major depressive disorder. A protocol for a randomised clinical trial

Directory of Open Access Journals (Sweden)

Jakobsen Janus Christian

2012-12-01

Full Text Available Abstract Background Most interventions for depression have shown small or no effects. ‘Third wave‘ cognitive therapy and mentalization-based therapy have both gained some ground as treatments of psychological problems. No randomised trial has compared the effects of these two interventions for patients with major depression. Methods/ design We plan a randomised, parallel group, assessor-blinded superiority clinical trial. During two years we will include 84 consecutive adult participants diagnosed with major depressive disorder. The participants will be randomised to either ‘third wave‘ cognitive therapy versus mentalization-based therapy. The primary outcome will be the Hamilton Rating Scale for Depression at cessation of treatment at 18 weeks. Secondary outcomes will be the proportion of patients with remission, Symptom Checklist 90 Revised, Beck’s Depression Inventory, and The World Health Organisation-Five Well-being Index 1999. Discussion Interventions for depression have until now shown relatively small effects. Our trial results will provide knowledge about the effects of two modern psychotherapeutic interventions. Trial registration ClinicalTrials: NCT01070134

Clinical Trials

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Full Text Available ... edge approaches, such as gene therapy or new biological treatments. Health insurance and health care providers don't ... of a trial, early if the strategy or treatment is having harmful effects. Food and Drug Administration In the United States, the Food and ...

A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

Science.gov (United States)

Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod; Gomez, Ana M; Flanigan, Kevin M; Lowes, Linda P; Alfano, Lindsay N; Berry, Katherine; Meadows, Eric; Lewis, Sarah; Braun, Lyndsey; Shontz, Kim; Rouhana, Maria; Clark, Kelly Reed; Rosales, Xiomara Q; Al-Zaidy, Samiah; Govoni, Alessandra; Rodino-Klapac, Louise R; Hogan, Mark J; Kaspar, Brian K

2015-01-01

Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3 × 10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6 × 10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases.

Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.

Science.gov (United States)

Lin, Ja-An; He, Pei

2015-06-01

Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement. © The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

Science.gov (United States)

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

Science.gov (United States)

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

Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial.

Science.gov (United States)

Tardieu, Marc; Zérah, Michel; Gougeon, Marie-Lise; Ausseil, Jérome; de Bournonville, Stéphanie; Husson, Béatrice; Zafeiriou, Dimitrios; Parenti, Giancarlo; Bourget, Philippe; Poirier, Béatrice; Furlan, Valérie; Artaud, Cécile; Baugnon, Thomas; Roujeau, Thomas; Crystal, Ronald G; Meyer, Christian; Deiva, Kumaran; Heard, Jean-Michel

2017-09-01

Mucopolysaccharidosis type IIIB syndrome (also known as Sanfilippo type B syndrome) is a lysosomal storage disease resulting in progressive deterioration of cognitive acquisition after age 2-4 years. No treatment is available for the neurological manifestations of the disease. We sought to assess the safety and efficacy of a novel intracerebral gene therapy. Local regulatory authorities in France allowed inclusion of up to four children in this phase 1/2 study. Treatment was 16 intraparenchymal deposits (four in the cerebellum) of a recombinant adenoassociated viral vector serotype 2/5 (rAAV2/5) encoding human α-N-acetylglucosaminidase (NAGLU) plus immunosuppressive therapy. We assessed tolerance, neurocognitive progression, brain growth, NAGLU enzymatic activity in CSF, and specific anti-NAGLU immune response for 30 months after surgery. This trial is registered with EudraCT, number 2012-000856-33, and the International Standard Clinical Trial Registry, number ISRCTN19853672. Of seven eligible children, the four youngest, from France (n=2), Italy (n=1), and Greece (n=1), aged 20, 26, 30, and 53 months, were included between February, 2012, and February, 2014. 125 adverse events were recorded, of which 117 were treatment emergent and included six classified as severe, but no suspected unexpected serious adverse drug reactions were seen. Vector genomes were detected in blood for 2 days after surgery. Compared with the natural history of mucopolysaccharidosis type III syndromes, neurocognitive progression was improved in all patients, with the youngest patient having function close to that in healthy children. Decrease in developmental quotient was -11·0 points in patient one, -23·0 in patient two, -29·0 in patient three, and -17·0 in patient four, compared with -37·7 in the natural history of the disease. NAGLU activity was detected in lumbar CSF and was 15-20% of that in unaffected children. Circulating T lymphocytes that proliferated and produced tumour

Prospects for Gene Therapy in the Fragile X Syndrome

Science.gov (United States)

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…

Results of two randomised clinical trials of neutron therapy in rectal adenocarcinoma

International Nuclear Information System (INIS)

Duncan, W.; Arnott, S.J.; Jack, W.J.L.; Orr, J.A.; Kerr, G.R.; Williams, J.R.

1987-01-01

Two clinical trials of neutron therapy were instituted to compare fast neutron therapy with megavoltage therapy in inoperable adenocarcinoma of the rectum and in postoperative recurrent adenocarcinoma of the rectum and to evaluate local tumour control, radiation morbidity and survival rates. In both rectal trials, complete local regression and persistent local control of tumour were similar in each treatment group. Survival was poor and so there is little long-term experience of tumour control and morbidity. The possibility that the relatively poor penetration of the neutron beam had an adverse effect on the results of neutron therapy should be considered. (Auth.)

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

Trojan horse at cellular level for tumor gene therapies.

Science.gov (United States)

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.

Science.gov (United States)

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.

Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial

Science.gov (United States)

Tendler, Rabbi Moshe D.; Loike, John D.

2015-01-01

The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal. PMID:26241230

Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial

Directory of Open Access Journals (Sweden)

Rabbi Moshe D. Tendler

2015-07-01

Full Text Available The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal.

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

Directory of Open Access Journals (Sweden)

S.V. Martini

2011-11-01

Full Text Available Gene therapy is an alternative treatment for genetic lung disease, especially monogenic disorders such as cystic fibrosis. Cystic fibrosis is a severe autosomal recessive disease affecting one in 2500 live births in the white population, caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR. The disease is classically characterized by pancreatic enzyme insufficiency, an increased concentration of chloride in sweat, and varying severity of chronic obstructive lung disease. Currently, the greatest challenge for gene therapy is finding an ideal vector to deliver the transgene (CFTR to the affected organ (lung. Adeno-associated virus is the most promising viral vector system for the treatment of respiratory disease because it has natural tropism for airway epithelial cells and does not cause any human disease. This review focuses on the basic properties of adeno-associated virus and its use as a vector for cystic fibrosis gene therapy.

TU-G-BRB-05: Panel Discussion: Clinical Trials in Proton and Ion Therapy - Are We Ready?

International Nuclear Information System (INIS)

Schulte, R.

2015-01-01

Proton therapy, in particular, and ion therapy, just beginning, are becoming an increasing focus of attention in clinical radiation oncology and medical physics. Both modalities have been criticized of lacking convincing evidence from randomized trials proving their efficacy, justifying the higher costs involved in these therapies. This session will provide an overview of the current status of clinical trials in proton therapy, including recent developments in ion therapy. As alluded to in the introductory talk by Dr. Schulte, opinions are diverging widely as to the usefulness and need for clinical trials in particle therapy and the challenge of equipoise. The lectures will highlight some of the challenges that surround clinical trials in particle therapy. One, presented by Dr. Choy from UT Southwestern, is that new technology and even different types of particles such as helium and carbon ions are introduced into this environment, increasing the phase space of clinical variables. The other is the issue of medical physics quality assurance with physical phantoms, presented by Mrs. Taylor from IROC Houston, which is more challenging because 3D and 4D image guidance and active delivery techniques are in relatively early stages of development. The role of digital phantoms in developing clinical treatment planning protocols and as a QA tool will also be highlighted by Dr. Lee from NCI. The symposium will be rounded off by a panel discussion among the Symposium speakers, arguing pro or con the need and readiness for clinical trials in proton and ion therapy. Learning Objectives: To get an update on the current status of clinical trials allowing or mandating proton therapy. Learn about the status of planned clinical trials in the U.S. and worldwide involving ion therapy. Discuss the challenges in the design and QA of clinical trials in particle therapy. Learn about existing and future physical and computational anthropomorphic phantoms for charged particle clinical trial

Combined anti-tumor necrosis factor-α therapy and DMARD therapy in rheumatoid arthritis patients reduces inflammatory gene expression in whole blood compared to DMARD therapy alone

Directory of Open Access Journals (Sweden)

Carl K Edwards

2012-12-01

Full Text Available Periodic assessment of gene expression for diagnosis and monitoring in rheumatoid arthritis (RA may provide a readily available and useful method to detect subclinical disease progression and follow responses to therapy with disease modifying anti-rheumatic agents (DMARDs or anti-TNF-α therapy. We used quantitative real-time PCR to compare peripheral blood gene expression profiles in active ("unstable" RA patients on DMARDs, stable RA patients on DMARDs, and stable RA patients treated with a combination of a DMARD and an anti-TNF-α agent (infliximab or etanercept to healthy human controls. The expression of 48 inflammatory genes were compared between healthy controls (N=122, unstable DMARD patients (N=18, stable DMARD patients (N=26, and stable patients on combination therapy (N=20. Expression of 13 genes was very low or undetectable in all study groups. Compared to healthy controls, patients with unstable RA on DMARDs exhibited increased expression of 25 genes, stable DMARD patients exhibited increased expression of 14 genes and decreased expression of five genes, and combined therapy patients exhibited increased expression of six genes and decreased expression of 10 genes. These findings demonstrate that active RA is associated with increased expression of circulating inflammatory markers whereas increases in inflammatory gene expression are diminished in patients with stable disease on either DMARD or anti-TNF-α therapy. Furthermore, combination DMARD and anti-TNF-α therapy is associated with greater reductions in circulating inflammatory gene expression compared to DMARD therapy alone. These results suggest that assessment of peripheral blood gene expression may prove useful to monitor disease progression and response to therapy.

Clinical Trials

Medline Plus

Full Text Available ... taking the same treatment the same way. These patients are closely watched by Data and Safety Monitoring Boards. Even if you don't directly ... risk procedures (such as gene therapy) or vulnerable patients (such as ... trial for safety problems or differences in results among different groups. ...

The interplay of post-translational modification and gene therapy

Directory of Open Access Journals (Sweden)

Osamor VC

2016-02-01

Full Text Available Victor Chukwudi Osamor,1–3 Shalom N Chinedu,3,4 Dominic E Azuh,3,5 Emeka Joshua Iweala,3,4 Olubanke Olujoke Ogunlana3,4 1Covenant University Bioinformatics Research (CUBRe Unit, Department of Computer and Information Sciences, College of Science and Technology (CST, Covenant University, Ota, Ogun State, Nigeria; 2Institute of Informatics (Computational biology and Bioinformatics, Faculty of Mathematics, Informatics and Mechanics, University of Warsaw (Uniwersytet Warszawski, Warszawa, Poland; 3Covenant University Public Health and Well-being Research Group (CUPHWERG, Covenant University, 4Biochemistry and Molecular Biology Unit, Department of Biological Sciences, College of Science and Technology, Covenant University, Canaan Land, 5Department of Economics and Development Studies, Covenant University, Ota, Ogun State, Nigeria Abstract: Several proteins interact either to activate or repress the expression of other genes during transcription. Based on the impact of these activities, the proteins can be classified into readers, modifier writers, and modifier erasers depending on whether histone marks are read, added, or removed, respectively, from a specific amino acid. Transcription is controlled by dynamic epigenetic marks with serious health implications in certain complex diseases, whose understanding may be useful in gene therapy. This work highlights traditional and current advances in post-translational modifications with relevance to gene therapy delivery. We report that enhanced understanding of epigenetic machinery provides clues to functional implication of certain genes/gene products and may facilitate transition toward revision of our clinical treatment procedure with effective fortification of gene therapy delivery. Keywords: post-translational modification, gene therapy, epigenetics, histone, methylation

Gene expression of osteogenic factors following gene therapy in mandibular lengthening.

Science.gov (United States)

Wu, Guoping; Zhou, Bin; Hu, Chunbing; Li, Shaolan

2015-03-01

This study investigated the effect of gene therapy on the expression of osteogenic mediators in mandibular distraction osteogenesis rabbits. Bilateral mandibular osteotomies were performed in 45 New-Zealand rabbits. After a latency of 3 days, the mandibles were elongated using distractors with a rate of 0.8 mm/d for 7 days. After the completion of distraction, the rabbits were randomly divided into 5 groups: 2 μg (0.1 μg/μL) of recombinant plasmid pIRES-hVEGF165-hBMP-2, recombinant plasmid pIRES-hBMP2, recombinant plasmid pIRES-hVEGF165, pIRES, and the same volume of normal saline were injected into the distraction gap of groups A, B, C, D, and E, respectively, followed by electroporation. Three animals were killed at the 7th, 14th, and 28th day after gene transfected in different groups, respectively. The lengthened mandibles were harvested and processed for immunohistochemical examinations; the mean optic densities (MODs) and integral optical density of bone morphogenetic protein (BMP-2) and transforming growth factor β1 (TGF-β1)-positive cells were measured by CMIAS-2001A computerized image analyzer. The data were analyzed with SPSS (SPSS Inc, Chicago, IL). Bone morphogenetic protein 2 and TGF-β1 staining was mainly located in inflammatory cells, monocytes, fibroblasts, osteoblasts, osteocytes, and chondrocytes in the distraction zones. Their strongest expression reached to the peak at the seventh day and decreased at the 14th day of consolidation stage; at the 28th day, they expressed weakly. Image analysis results show that, at the seventh day, the expression of BMP-2 in group B (0.26 ± 0.03, 0.36 ± 0.02) was the strongest; there was significant difference among them (P < 0.01), whereas the expression of TGF-β1 in group C (0.38 ± 0.06, 1.05 ± 0.19) is strongest followed by group A (0.34 ± 0.05, 0.95 ± 0.16) and B (0.33 ± 0.07, 0.90 ± 0.19). At every time point, the level of expression of BMP-2 and TGF-β1 in gene therapy groups (groups A, B, and

Anti-tumor effects of Egr-IFN gamma gene therapy combined with {sup 125}I-UdR radionuclide therapy

Energy Technology Data Exchange (ETDEWEB)

Jingguo, Zhao [No.403 Hospital of PLA, Dalian (China); Yanjun, Ni; Xiangfu, Song; Yanyi, Li; Wei, Yang; Ting, Sun; Qingjie, Ma; Fengtong, Gao

2008-12-15

Objective: To explore the anti-tumor effects of Egr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNgamma mixed with liposome was injected into tumor. 48 h later, 370 kBq {sup 125}I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNgamma in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNgamma + {sup 125}I-UdR group were obviously lower than those of control group, {sup 125}I-UdR group and pcDNAEgr-1 + {sup 125}I-UdR group 6-15 d after gene-radionuclide therapy. IFNgamma protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNgamma + {sup 125}I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNgamma + {sup 125}I-UdR group was significantly higher than that in the other groups (P<0.01). Conclusions: The anti-tumor effects in vivo of pcDNAEgr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy are better than those of {sup 125}I-UdR therapy. (authors)

Ethics of Gene Therapy Debated.

Science.gov (United States)

Borman, Stu

1991-01-01

Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

Status and advances of p53-gene therapy and radiotherapy in malignant tumor

International Nuclear Information System (INIS)

Duan Xin; Chinese Academy of Sciences, Beijing; Zhang Hong

2006-01-01

Cancer treatment is one of the most important fields in medical research. All strategies such as radio-therapy, chemotherapy, surgery, and gene-based therapy have their own advantages and disadvantages. Nowadays, a novel method which combined p53-gene therapy with radiotherapy plays an important role in the field of cancer research. This review summarized the current state of combined therapies of p53-gene therapy and radiotherapy, possible mechanism and recent progress. (authors)

78 FR 44133 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-07-23

...] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the Committee: To provide... documents issued from the Office of Cellular, Tissue and Gene Therapies, Center for Biologics Evaluation and...

76 FR 22405 - Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting

Science.gov (United States)

2011-04-21

...] Cellular, Tissue and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Cellular, Tissue and Gene Therapies Advisory Committee. General Function of the Committee: To provide... June 29, 2011, the committee will discuss cellular and gene therapy products for the treatment of...

78 FR 79699 - Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting

Science.gov (United States)

2013-12-31

...] Cellular, Tissue, and Gene Therapies Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Cellular, Tissue, and Gene Therapies Advisory Committee. General Function of the Committee: To provide... updates on guidance documents issued from the Office of Cellular, Tissue, and Gene Therapies, Center for...

Virotherapy: cancer gene therapy at last? [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Alan E. Bilsland

2016-08-01

Full Text Available For decades, effective cancer gene therapy has been a tantalising prospect; for a therapeutic modality potentially able to elicit highly effective and selective responses, definitive efficacy outcomes have often seemed out of reach. However, steady progress in vector development and accumulated experience from previous clinical studies has finally led the field to its first licensed therapy. Following a pivotal phase III trial, Imlygic (talimogene laherparepvec/T-Vec received US approval as a treatment for cutaneous and subcutaneous melanoma in October 2015, followed several weeks later by its European authorisation. These represent the first approvals for an oncolytic virotherapy. Imlygic is an advanced-generation herpesvirus-based vector optimised for oncolytic and immunomodulatory activities. Many other oncolytic agents currently remain in development, providing hope that current success will be followed by other diverse vectors that may ultimately come to constitute a new class of clinical anti-cancer agents. In this review, we discuss some of the key oncolytic viral agents developed in the adenovirus and herpesvirus classes, and the prospects for further enhancing their efficacy by combining them with novel immunotherapeutic approaches.

Update on gene therapy of inherited immune deficiencies.

Science.gov (United States)

Engel, Barbara C; Kohn, Donald B; Podsakoff, Greg M

2003-10-01

Gene therapy has been under development as a way to correct inborn errors for many years. Recently, patients with two forms of inherited severe combined immunodeficiency (SCID), adenosine deaminase and X-linked, treated by three different clinical investigative teams, have shown significant immune reconstitution leading to protective immunity. These advances irrefutably prove the concept that hematopoietic progenitor cell gene therapy can ameliorate these diseases. However, due to proviral insertional oncogenesis, two individuals in one of the X-SCID studies developed T-cell leukemia more than two years after the gene transfer. Depending upon the results of long-term follow-up, the successes together with the side effects highlight the relative merits of this therapeutic approach.

Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies.

Science.gov (United States)

Nichols, T C; Hough, C; Agersø, H; Ezban, M; Lillicrap, D

2016-05-01

Animal models of inherited bleeding disorders are important for understanding disease pathophysiology and are required for preclinical assessment of safety prior to testing of novel therapeutics in human and veterinary medicine. Experiments in these animals represent important translational research aimed at developing safer and better treatments, such as plasma-derived and recombinant protein replacement therapies, gene therapies and immune tolerance protocols for antidrug inhibitory antibodies. Ideally, testing is done in animals with the analogous human disease to provide essential safety information, estimates of the correct starting dose and dose response (pharmacokinetics) and measures of efficacy (pharmacodynamics) that guide the design of human trials. For nearly seven decades, canine models of hemophilia, von Willebrand disease and other inherited bleeding disorders have not only informed our understanding of the natural history and pathophysiology of these disorders but also guided the development of novel therapeutics for use in humans and dogs. This has been especially important for the development of gene therapy, in which unique toxicities such as insertional mutagenesis, germ line gene transfer and viral toxicities must be assessed. There are several issues regarding comparative medicine in these species that have a bearing on these studies, including immune reactions to xenoproteins, varied metabolism or clearance of wild-type and modified proteins, and unique tissue tropism of viral vectors. This review focuses on the results of studies that have been performed in dogs with inherited bleeding disorders that closely mirror the human condition to develop safe and effective protein and gene-based therapies that benefit both species. © 2016 International Society on Thrombosis and Haemostasis.

Anti-tumor effects of Egr-IFN γ gene therapy combined with 125I-UdR radionuclide therapy

International Nuclear Information System (INIS)

Zhao Jingguo; Ni Yanjun; Song Xiangfu; Li Yanyi; Yang Wei; Sun Ting; Ma Qingjie; Gao Fengtong

2008-01-01

Objective: To explore the anti-tumor effects of Egr-IFNγ gene therapy combined with 125 I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNγ mixed with liposome was injected into tumor. 48 h later, 370 kBq 125 I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNγ in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNγ + 125 I-UdR group were obviously lower than those of control group, 125 I-UdR group and pcDNAEgr-1 + 125 I-UdR group 6-15 d after gene-radionuclide therapy. IFNγ protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNγ + 125 I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNγ + 125 I-UdR group was significantly higher than that in the other groups (P 125 I-UdR radionuclide therapy are better than those of 125 I-UdR therapy. (authors)

Most Trial Eligibility Criteria and Patient Baseline Characteristics Do Not Modify Treatment Effect in Trials Using Targeted Therapies for Rheumatoid Arthritis

DEFF Research Database (Denmark)

Christensen, Anton Wulf; Tarp, Simon; Furst, Daniel E

2015-01-01

OBJECTIVE: To determine if variations in trial eligibility criteria and patient baseline characteristics could be considered effect modifiers of the treatment response when testing targeted therapies (biological agents and targeted synthetic disease modifying antirheumatic drugs (DMARDs....... Odds ratios (ORs) were calculated from the response rates and compared among the trial eligibility criteria/patient baseline characteristics of interest. Comparisons are presented as the Ratio of Odds Ratios (ROR). RESULTS: Sixty-two trials (19,923 RA patients) were included in the primary analyses...... using ACR20 response. Overall, targeted therapies constituted an effective treatment (OR 3.96 95% confidence interval (CI) 3.41 to 4.60). The majority of the trial eligibility criteria and patient baseline characteristics did not modify treatment effect. The added benefit of targeted therapies was lower...

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.

77 FR 65693 - Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice

Science.gov (United States)

2012-10-30

...] Cellular, Tissue and Gene Therapies Advisory Committee; Amendment of Notice AGENCY: Food and Drug... notice of a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee. This meeting was... announced that a meeting of the Cellular, Tissue and Gene Therapies Advisory Committee would be held on...

Genetic correction using engineered nucleases for gene therapy applications.

Science.gov (United States)

Li, Hongmei Lisa; Nakano, Takao; Hotta, Akitsu

2014-01-01

Genetic mutations in humans are associated with congenital disorders and phenotypic traits. Gene therapy holds the promise to cure such genetic disorders, although it has suffered from several technical limitations for decades. Recent progress in gene editing technology using tailor-made nucleases, such as meganucleases (MNs), zinc finger nucleases (ZFNs), TAL effector nucleases (TALENs) and, more recently, CRISPR/Cas9, has significantly broadened our ability to precisely modify target sites in the human genome. In this review, we summarize recent progress in gene correction approaches of the human genome, with a particular emphasis on the clinical applications of gene therapy. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

Randomized Trial of Asprin as Adjuvant Therapy for Node-Positive Breast Cancer

Science.gov (United States)

2017-10-01

AWARD NUMBER: W81XWH-15-1-0268 TITLE: Randomized Trial of Asprin as Adjuvant Therapy for Node-Positive Breast Cancer PRINCIPAL INVESTIGATOR...Eric Winer CONTRACTING ORGANIZATION: Dana-Farber Cancer Institute Boston, MA 02215 REPORT DATE: OCTOBER 2017 TYPE OF REPORT: ANNUAL PREPARED FOR...CONTRACT NUMBER Randomized Trial of Asprin as Adjuvant Therapy for Node- Positive Breast Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR

Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma.

Science.gov (United States)

Abdelaziz, Mohamed; Sherif, Lotfy; ElKhiary, Mostafa; Nair, Sanjeeta; Shalaby, Shahinaz; Mohamed, Sara; Eziba, Noura; El-Lakany, Mohamed; Curiel, David; Ismail, Nahed; Diamond, Michael P; Al-Hendy, Ayman

2016-04-01

Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P leiomyoma lesions with both targeted and untargeted adenovirus. Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial. © The Author(s) 2016.

OpenGeneMed: a portable, flexible and customizable informatics hub for the coordination of next-generation sequencing studies in support of precision medicine trials.

Science.gov (United States)

Palmisano, Alida; Zhao, Yingdong; Li, Ming-Chung; Polley, Eric C; Simon, Richard M

2017-09-01

Trials involving genomic-driven treatment selection require the coordination of many teams interacting with a great variety of information. The need of better informatics support to manage this complex set of operations motivated the creation of OpenGeneMed. OpenGeneMed is a stand-alone and customizable version of GeneMed (Zhao et al. GeneMed: an informatics hub for the coordination of next-generation sequencing studies that support precision oncology clinical trials. Cancer Inform 2015;14(Suppl 2):45), a web-based interface developed for the National Cancer Institute Molecular Profiling-based Assignment of Cancer Therapy (NCI-MPACT) clinical trial coordinated by the NIH. OpenGeneMed streamlines clinical trial management and it can be used by clinicians, lab personnel, statisticians and researchers as a communication hub. It automates the annotation of genomic variants identified by sequencing tumor DNA, classifies the actionable mutations according to customizable rules and facilitates quality control in reviewing variants. The system generates summarized reports with detected genomic alterations that a treatment review team can use for treatment assignment. OpenGeneMed allows collaboration to happen seamlessly along the clinical pipeline; it helps reduce errors made transferring data between groups and facilitates clear documentation along the pipeline. OpenGeneMed is distributed as a stand-alone virtual machine, ready for deployment and use from a web browser; its code is customizable to address specific needs of different clinical trials and research teams. Examples on how to change the code are provided in the technical documentation distributed with the virtual machine. In summary, OpenGeneMed offers an initial set of features inspired by our experience with GeneMed, a system that has been proven to be efficient and successful for coordinating the application of next-generation sequencing in the NCI-MPACT trial. Published by Oxford University Press 2016. This

Molecular MR imaging of cancer gene therapy. Ferritin transgene reporter takes the stage

International Nuclear Information System (INIS)

Hasegawa, Sumitaka; Furukawa, Takako; Saga, Tsuneo

2010-01-01

Molecular imaging using magnetic resonance (MR) imaging has been actively investigated and made rapid progress in the past decade. Applied to cancer gene therapy, the technique's high spatial resolution allows evaluation of gene delivery into target tissues. Because noninvasive monitoring of the duration, location, and magnitude of transgene expression in tumor tissues or cells provides useful information for assessing therapeutic efficacy and optimizing protocols, molecular imaging is expected to become a critical step in the success of cancer gene therapy in the near future. We present a brief overview of the current status of molecular MR imaging, especially in vivo reporter gene imaging using ferritin and other reporters, discuss its application to cancer gene therapy, and present our research of MR imaging detection of electroporation-mediated cancer gene therapy using the ferritin reporter gene. (author)

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...

Neurotrophin gene therapy for sustained neural preservation after deafness.

Science.gov (United States)

Atkinson, Patrick J; Wise, Andrew K; Flynn, Brianna O; Nayagam, Bryony A; Hume, Clifford R; O'Leary, Stephen J; Shepherd, Robert K; Richardson, Rachael T

2012-01-01

The cochlear implant provides auditory cues to profoundly deaf patients by electrically stimulating the residual spiral ganglion neurons. These neurons, however, undergo progressive degeneration after hearing loss, marked initially by peripheral fibre retraction and ultimately culminating in cell death. This research aims to use gene therapy techniques to both hold and reverse this degeneration by providing a sustained and localised source of neurotrophins to the deafened cochlea. Adenoviral vectors containing green fluorescent protein, with or without neurotrophin-3 and brain derived neurotrophic factor, were injected into the lower basal turn of scala media of guinea pigs ototoxically deafened one week prior to intervention. This single injection resulted in localised and sustained gene expression, principally in the supporting cells within the organ of Corti. Guinea pigs treated with adenoviral neurotrophin-gene therapy had greater neuronal survival compared to contralateral non-treated cochleae when examined at 7 and 11 weeks post injection. Moreover; there was evidence of directed peripheral fibre regrowth towards cells expressing neurotrophin genes after both treatment periods. These data suggest that neurotrophin-gene therapy can provide sustained protection of spiral ganglion neurons and peripheral fibres after hearing loss.

Advances of reporter gene imaging monitoring stem cell therapy

International Nuclear Information System (INIS)

Pei Zhijun; Zhang Yongxue

2010-01-01

Stem cell transplantation in the treatment of various tissue damage or degenerative diseases are research hotspots both at home and abroad. However, ignorance of the homing, differentiation and functional expression of the stem cell in vivo influence the further development of stem cell therapy. As an important component of molecular imaging technology, reporter gene imaging dynamically monitors the change of stem cell in vivo via monitoring the expression of transfected reporter gene. This paper briefly describes the latest research progress and the future development trend of the monitoring of reporter gene imaging in stem cell therapy in vivo. (authors)

A Randomized Controlled Trial of Acceptance-Based Behavior Therapy and Cognitive Therapy for Test Anxiety: A Pilot Study

Science.gov (United States)

Brown, Lily A.; Forman, Evan M.; Herbert, James D.; Hoffman, Kimberly L.; Yuen, Erica K.; Goetter, Elizabeth M.

2011-01-01

Many university students suffer from test anxiety that is severe enough to impair performance. Given mixed efficacy results of previous cognitive-behavior therapy (CBT) trials and a theoretically driven rationale, an acceptance-based behavior therapy (ABBT) approach was compared to traditional CBT (i.e., Beckian cognitive therapy; CT) for the…

Perspective on Adeno-Associated Virus Capsid Modification for Duchenne Muscular Dystrophy Gene Therapy.

Science.gov (United States)

Nance, Michael E; Duan, Dongsheng

2015-12-01

Duchenne muscular dystrophy (DMD) is a X-linked, progressive childhood myopathy caused by mutations in the dystrophin gene, one of the largest genes in the genome. It is characterized by skeletal and cardiac muscle degeneration and dysfunction leading to cardiac and/or respiratory failure. Adeno-associated virus (AAV) is a highly promising gene therapy vector. AAV gene therapy has resulted in unprecedented clinical success for treating several inherited diseases. However, AAV gene therapy for DMD remains a significant challenge. Hurdles for AAV-mediated DMD gene therapy include the difficulty to package the full-length dystrophin coding sequence in an AAV vector, the necessity for whole-body gene delivery, the immune response to dystrophin and AAV capsid, and the species-specific barriers to translate from animal models to human patients. Capsid engineering aims at improving viral vector properties by rational design and/or forced evolution. In this review, we discuss how to use the state-of-the-art AAV capsid engineering technologies to overcome hurdles in AAV-based DMD gene therapy.

Physiotherapy and Occupational Therapy vs No Therapy in Mild to Moderate Parkinson Disease: A Randomized Clinical Trial.

Science.gov (United States)

Clarke, Carl E; Patel, Smitaa; Ives, Natalie; Rick, Caroline E; Dowling, Francis; Woolley, Rebecca; Wheatley, Keith; Walker, Marion F; Sackley, Catherine M

2016-03-01

It is unclear whether physiotherapy and occupational therapy are clinically effective and cost-effective in Parkinson disease (PD). To perform a large pragmatic randomized clinical trial to evaluate the clinical effectiveness of individualized physiotherapy and occupational therapy in PD. The PD REHAB Trial was a multicenter, open-label, parallel group, controlled efficacy trial. A total of 762 patients with mild to moderate PD were recruited from 38 sites across the United Kingdom. Recruitment took place between October 2009 and June 2012, with 15 months of follow-up. Participants with limitations in activities of daily living (ADL) were randomized to physiotherapy and occupational therapy or no therapy. The primary outcome was the Nottingham Extended Activities of Daily Living (NEADL) Scale score at 3 months after randomization. Secondary outcomes were health-related quality of life (assessed by Parkinson Disease Questionnaire-39 and EuroQol-5D); adverse events; and caregiver quality of life. Outcomes were assessed before trial entry and then 3, 9, and 15 months after randomization. Of the 762 patients included in the study (mean [SD] age, 70 [9.1] years), 381 received physiotherapy and occupational therapy and 381 received no therapy. At 3 months, there was no difference between groups in NEADL total score (difference, 0.5 points; 95% CI, -0.7 to 1.7; P = .41) or Parkinson Disease Questionnaire-39 summary index (0.007 points; 95% CI, -1.5 to 1.5; P = .99). The EuroQol-5D quotient was of borderline significance in favor of therapy (-0.03; 95% CI, -0.07 to -0.002; P = .04). The median therapist contact time was 4 visits of 58 minutes over 8 weeks. Repeated-measures analysis showed no difference in NEADL total score, but Parkinson Disease Questionnaire-39 summary index (diverging 1.6 points per annum; 95% CI, 0.47 to 2.62; P = .005) and EuroQol-5D score (0.02; 95% CI, 0.00007 to 0.03; P = .04) showed small differences in favor of therapy. There was no difference in

Art Therapy and Cognitive Processing Therapy for Combat-Related PTSD: A Randomized Controlled Trial

Science.gov (United States)

Campbell, Melissa; Decker, Kathleen P.; Kruk, Kerry; Deaver, Sarah P.

2018-01-01

This randomized controlled trial was designed to determine if art therapy in conjunction with Cognitive Processing Therapy (CPT) was more effective for reducing symptoms of combat posttraumatic stress disorder (PTSD) than CPT alone. Veterans (N = 11) were randomized to receive either individual CPT, or individual CPT in conjunction with individual art therapy. PTSD Checklist–Military Version and Beck Depression Inventory–II scores improved with treatment in both groups with no significant difference in improvement between the experimental and control groups. Art therapy in conjunction with CPT was found to improve trauma processing and veterans considered it to be an important part of their treatment as it provided healthy distancing, enhanced trauma recall, and increased access to emotions. PMID:29332989

Gene Therapy for Chronic HBV-Can We Eliminate cccDNA?

Science.gov (United States)

Bloom, Kristie; Maepa, Mohube Betty; Ely, Abdullah; Arbuthnot, Patrick

2018-04-12

Chronic infection with the hepatitis B virus (HBV) is a global health concern and accounts for approximately 1 million deaths annually. Amongst other limitations of current anti-HBV treatment, failure to eliminate the viral covalently closed circular DNA (cccDNA) and emergence of resistance remain the most worrisome. Viral rebound from latent episomal cccDNA reservoirs occurs following cessation of therapy, patient non-compliance, or the development of escape mutants. Simultaneous viral co-infections, such as by HIV-1, further complicate therapeutic interventions. These challenges have prompted development of novel targeted hepatitis B therapies. Given the ease with which highly specific and potent nucleic acid therapeutics can be rationally designed, gene therapy has generated interest for antiviral application. Gene therapy strategies developed for HBV include gene silencing by harnessing RNA interference, transcriptional inhibition through epigenetic modification of target DNA, genome editing by designer nucleases, and immune modulation with cytokines. DNA-binding domains and effectors based on the zinc finger (ZF), transcription activator-like effector (TALE), and clustered regularly interspaced short palindromic repeat (CRISPR) systems are remarkably well suited to targeting episomal cccDNA. This review discusses recent developments and challenges facing the field of anti-HBV gene therapy, its potential curative significance and the progress towards clinical application.

Fight fire with fire: Gene therapy strategies to cure HIV.

Science.gov (United States)

Huyghe, Jon; Magdalena, Sips; Vandekerckhove, Linos

2017-08-01

Human Immunodeficiency Virus (HIV) to date remains one of the most notorious viruses mankind has ever faced. Despite enormous investments in HIV research for more than 30 years an effective cure for HIV has been elusive. Areas covered: Combination antiretroviral therapy (cART) suppresses active viral replication, but is not able to eliminate the virus completely due to stable integration of HIV inside the host genome of infected cells and the establishment of a latent reservoir, that is insensitive to cART. Nevertheless, this latent HIV reservoir is fully capable to refuel viral replication when treatment is stopped, creating a major obstacle towards a cure for HIV. Several gene therapy approaches ranging from the generation of HIV resistant CD4 + T cells to the eradication of HIV infected cells by immune cell engineering are currently under pre-clinical and clinical investigation and may present a promising road to a cure. In this review, we focus on the status and the prospects of gene therapy strategies to cure/eradicate HIV. Expert commentary: Recent advances in gene therapy for oncology and infectious diseases indicate that gene therapy may be a feasible and very potent cure strategy, and therefore a potential game changer in the search for an effective HIV cure.

Neonatal tolerance induction enables accurate evaluation of gene therapy for MPS I in a canine model.

Science.gov (United States)

Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre; Katz, Nathan; Zhu, Yanqing; Lin, Gloria; Choa, Ruth; Bagel, Jessica; O'Donnell, Patricia; Fitzgerald, Caitlin A; Langan, Therese; Wang, Ping; Casal, Margret L; Haskins, Mark E; Wilson, James M

2016-09-01

High fidelity animal models of human disease are essential for preclinical evaluation of novel gene and protein therapeutics. However, these studies can be complicated by exaggerated immune responses against the human transgene. Here we demonstrate that dogs with a genetic deficiency of the enzyme α-l-iduronidase (IDUA), a model of the lysosomal storage disease mucopolysaccharidosis type I (MPS I), can be rendered immunologically tolerant to human IDUA through neonatal exposure to the enzyme. Using MPS I dogs tolerized to human IDUA as neonates, we evaluated intrathecal delivery of an adeno-associated virus serotype 9 vector expressing human IDUA as a therapy for the central nervous system manifestations of MPS I. These studies established the efficacy of the human vector in the canine model, and allowed for estimation of the minimum effective dose, providing key information for the design of first-in-human trials. This approach can facilitate evaluation of human therapeutics in relevant animal models, and may also have clinical applications for the prevention of immune responses to gene and protein replacement therapies. Copyright © 2016 Elsevier Inc. All rights reserved.

Subthalamic hGAD65 Gene Therapy and Striatum TH Gene Transfer in a Parkinson’s Disease Rat Model

Science.gov (United States)

Zheng, Deyu; Jiang, Xiaohua; Zhao, Junpeng; Duan, Deyi; Zhao, Huanying; Xu, Qunyuan

2013-01-01

The aim of the present study is to detect a combination method to utilize gene therapy for the treatment of Parkinson’s disease (PD). Here, a PD rat model is used for the in vivo gene therapy of a recombinant adeno-associated virus (AAV2) containing a human glutamic acid decarboxylase 65 (rAAV2-hGAD65) gene delivered to the subthalamic nucleus (STN). This is combined with the ex vivo gene delivery of tyrosine hydroxylase (TH) by fibroblasts injected into the striatum. After the treatment, the rotation behavior was improved with the greatest efficacy in the combination group. The results of immunohistochemistry showed that hGAD65 gene delivery by AAV2 successfully led to phenotypic changes of neurons in STN. And the levels of glutamic acid and GABA in the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) were obviously lower than the control groups. However, hGAD65 gene transfer did not effectively protect surviving dopaminergic neurons in the SNc and VTA. This study suggests that subthalamic hGAD65 gene therapy and combined with TH gene therapy can alleviate symptoms of the PD model rats, independent of the protection the DA neurons from death. PMID:23738148

Anti-EGFR immunonanoparticles containing IL12 and salmosin genes for targeted cancer gene therapy.

Science.gov (United States)

Kim, Jung Seok; Kang, Seong Jae; Jeong, Hwa Yeon; Kim, Min Woo; Park, Sang Il; Lee, Yeon Kyung; Kim, Hong Sung; Kim, Keun Sik; Park, Yong Serk

2016-09-01

Tumor-directed gene delivery is of major interest in the field of cancer gene therapy. Varied functionalizations of non-viral vectors have been suggested to enhance tumor targetability. In the present study, we prepared two different types of anti-EGF receptor (EGFR) immunonanoparticles containing pDNA, neutrally charged liposomes and cationic lipoplexes, for tumor-directed transfection of cancer therapeutic genes. Even though both anti-EGFR immunonanoparticles had a high binding affinity to the EGFR-positive cancer cells, the anti-EGFR immunolipoplex formulation exhibited approximately 100-fold higher transfection to the target cells than anti-EGFR immunoliposomes. The lipoplex formulation also showed a higher transfection to SK-OV-3 tumor xenografts in mice. Thus, IL12 and/or salmosin genes were loaded in the anti-EGFR immunolipoplexes and intravenously administered to mice carrying SK-OV-3 tumors. Co-transfection of IL12 and salmosin genes using anti-EGFR immunolipoplexes significantly reduced tumor growth and pulmonary metastasis. Furthermore, combinatorial treatment with doxorubicin synergistically inhibited tumor growth. These results suggest that anti-EGFR immunolipoplexes containing pDNA encoding therapeutic genes could be utilized as a gene-transfer modality for cancer gene therapy.

78 FR 70307 - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

Science.gov (United States)

2013-11-25

...] Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products... Assessment of Investigational Cellular and Gene Therapy Products'' dated November 2013. The guidance document... products reviewed by the Office of Cellular, Tissue and Gene Therapies (OCTGT). The product areas covered...

A systematic review of randomized controlled trials using music therapy for children.

Science.gov (United States)

Mrázová, Marcela; Celec, Peter

2010-10-01

Music therapy is a promising approach widening the potential applications of psychotherapy. Music influences both, psychologic and physiologic parameters, and children are especially responsive to this form of therapy. Many aspects of its action mechanisms remain to be elucidated, underscoring the need for evidence-based medicine (EBM) for clinical use of music therapy. This review seeks to highlight some of the issues of music therapy research and to initiate a discussion about the need for international multicenter cooperation to bring scientifically sound evidence of the benefits of music therapy in pediatric patients. Scientific bibliographic databases were searched for randomized controlled trials on use of music therapy for children. Identified articles were evaluated according to criteria for scientific quality. Twenty-eight studies were identified. Most of the trials were biased by the number of participants, and some trials showed the need to improve design of control groups. Indeed, the novelty of this area of study has produced a large number of different studies (with variability in diagnoses, interventions, control groups, duration, and/or outcome parameters), and there is a need for a more homogeneous and systematic approach. Available studies highlight the need to address reproducibility issues. This analysis identifies the need for a subsequent series of clinical studies on the efficacy of music in the pediatric population, with more focus on eligibility criteria with respect to EBM and reproducibility.

A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor Temsirolimus added to standard therapy of Rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma – the STORM trial

International Nuclear Information System (INIS)

Witzens-Harig, Mathias; Memmer, Marie Luise; Dreyling, Martin; Hess, Georg

2013-01-01

The current standard treatment of patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL) primarily consists of intensified salvage therapy and, if the disease is chemo-sensitive, high dose therapy followed with autologous stem cell transplantation. In the rituximab era however, this treatment approach has shown only limited benefit. In particular, patients relapsing after rituximab-containing primary treatment have an adverse prognosis, especially if this occurs within the first year after therapy or if the disease is primarily refractory. Therefore there is an ultimate need for improved salvage treatment approaches. The STORM study is a prospective, multicentre phase I/II study to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to the standard therapy rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. The primary objective of the phase I of the trial is to establish the maximum tolerated dose (MTD) of temsirolimus in combination with rituximab and DHAP. The secondary objective is to demonstrate that stem cells can be mobilized during this regimen in patients scheduled to proceed to high dose therapy. In phase II, the previously established maximum tolerated dose of temsirolimus will be used. The primary objective is to evaluate the overall response rate (ORR) in patients with relapsed DLBCL. The secondary objective is to evaluate progression free survival (PFS), overall survival (OS) and toxicity. The study will be accompanied by an analysis of lymphoma subtypes determined by gene expression analysis (GEP). The STORM trial evaluates the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory DLBCL. It also might identify predictive markers for this treatment modality. ClinicalTrials.gov http

Efficacy and toxicity of replication-competent adenovirus-mediated double suicide gene therapy in combination with radiation therapy in an orthotopic mouse prostate cancer model

International Nuclear Information System (INIS)

Freytag, Svend O.; Paielli, Dell; Wing, Mark; Rogulski, Ken; Brown, Steve; Kolozsvary, Andy; Seely, John; Barton, Ken; Dragovic, Alek; Kim, Jae Ho

2002-01-01

, trimodal therapy was associated with little toxicity. A comparison of the major histopathologic findings among the treatment groups indicated that most of the locoregional (prostate, seminal vesicles, urinary bladder) pathology was attributable to the combined effects of the Ad5-CD/TKrep vector and EBRT and that the prodrugs contributed little to this effect. Importantly, trimodal therapy did not exacerbate inflammation of the rectum and intestines beyond that of EBRT alone. Conclusion: Together, the results support the thesis that replication-competent adenovirus-mediated double suicide gene therapy may be a safe and effective adjuvant to EBRT and provide a sound scientific rationale for human trials

Advances of reporter gene monitoring stem cell therapy

International Nuclear Information System (INIS)

Zhou Xiang; Yin Hongyan; Zhang Yifan

2010-01-01

Stem cell therapy research has made great progress, demonstrating a broad application prospects. However, stem cell therapy as a new disease treatment, there are still many problems to be solved. Reporter gene imaging is a rapid development in recent years, a non-invasive, sensitive method of monitoring of stem cells, in particular radionuclide reporter gene imaging has high sensitivity and specificity of the advantages of strong and can carry out imaging of deep tissue and repeat imaging, is a tracer in vivo conditions, the most promising stem cell transplantation technique, showing good prospects for development. (authors)

Non-viral gene therapy for bone tissue engineering.

Science.gov (United States)

Wegman, Fiona; Oner, F Cumhur; Dhert, Wouter J A; Alblas, Jacqueline

2013-01-01

The possibilities of using gene therapy for bone regeneration have been extensively investigated. Improvements in the design of new transfection agents, combining vectors and delivery/release systems to diminish cytotoxicity and increase transfection efficiencies have led to several successful in vitro, ex vivo and in vivo strategies. These include growth factor or short interfering ribonucleic acid (siRNA) delivery, or even enzyme replacement therapies, and have led to increased osteogenic differentiation and bone formation in vivo. These results provide optimism to consider use in humans with some of these gene-delivery strategies in the near future.

Molecular Imaging of Gene Expression and Efficacy following Adenoviral-Mediated Brain Tumor Gene Therapy

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Alnawaz Rehemtulla

2002-01-01

Full Text Available Cancer gene therapy is an active area of research relying upon the transfer and subsequent expression of a therapeutic transgene into tumor cells in order to provide for therapeutic selectivity. Noninvasive assessment of therapeutic response and correlation of the location, magnitude, and duration of transgene expression in vivo would be particularly useful in the development of cancer gene therapy protocols by facilitating optimization of gene transfer protocols, vector development, and prodrug dosing schedules. In this study, we developed an adenoviral vector containing both the therapeutic transgene yeast cytosine deaminase (yCD along with an optical reporter gene (luciferase. Following intratumoral injection of the vector into orthotopic 9L gliomas, anatomical and diffusion-weighted MR images were obtained over time in order to provide for quantitative assessment of overall therapeutic efficacy and spatial heterogeneity of cell kill, respectively. In addition, bioluminescence images were acquired to assess the duration and magnitude of gene expression. MR images revealed significant reduction in tumor growth rates associated with yCD/5-fluorocytosine (5FC gene therapy. Significant increases in mean tumor diffusion values were also observed during treatment with 5FC. Moreover, spatial heterogeneity in tumor diffusion changes were also observed revealing that diffusion magnetic resonance imaging could detect regional therapeutic effects due to the nonuniform delivery and/or expression of the therapeutic yCD transgene within the tumor mass. In addition, in vivo bioluminescence imaging detected luciferase gene expression, which was found to decrease over time during administration of the prodrug providing a noninvasive surrogate marker for monitoring gene expression. These results demonstrate the efficacy of the yCD/5FC strategy for the treatment of brain tumors and reveal the feasibility of using multimodality molecular and functional imaging

Advances in gene therapy of myocardial ischemia and the monitoring with molecular imaging

International Nuclear Information System (INIS)

Zhang Guopeng; Zhang Yongxue

2008-01-01

Cardiovascular diseases are harmful for people. Recent advances in understanding the molecular basis of cardiovascular diseases, together with some studies of the gene therapy on cardiovascular disorders, have offered possibilities for new treatments. Gene therapies have demonstrated potential usefulness in treating myocardial ischemia. Therefore, the monitoring of the expression of therapy gene and therapeutic efficacy has become an important issue. (authors)

Radiation Therapy Oncology Group clinical trials with misonidazole

International Nuclear Information System (INIS)

Wasserman, T.H.; Stetz, J.; Phillips, T.L.

1981-01-01

This paper presents a review of the progressive clinical trials of the hypoxic cell radiosensitizer, misonidazole, in the Radiation Therapy Oncology Group (RTOG). Presentation is made of all the schemas of the recently completed and currently active RTOG Phase II and Phase III studies. Detailed information is provided on the clinical toxicity of the Phase II trials, specifically regarding neurotoxicity. With limitations in drug total dose, a variety of dose schedules have proven to be tolerable, with a moderate incidence of nausea and vomiting and mild peripheral neuropathy or central neuropathy. No other organ toxicity has been seen, specifically no liver, renal or bone marrow toxicities. An additional Phase III malignant glioma trial in the Brain Tumor Study Group is described

Abnormal P-53 suppressor gene expression predicts for a poorer outcome in patients with locally advanced adenocarcinoma of the prostate treated by external beam radiation therapy with or without pre-radiation androgen ablation: results based on RTOG study 86-10

International Nuclear Information System (INIS)

Lawton, Colleen A.; Grignon, David; Caplan, Richard; Sarkar, Fazlul; Forman, Jeffrey; Mesic, John; Fu, Karen K.; Abrams, Ross

1995-01-01

Purpose/Objective: The purpose of this study is to establish the effect of the abnormal expression of the P-53 suppressor gene on the results of locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation. Materials and Methods: Patients evaluated were part of a RTOG phase III multi-institutional trial. This trial assessed the value of pre-radiation therapy androgen ablation on patients with locally advanced disease (bulky stage B and stage C). Of the 471 patients registered, pre-treatment pathological material was available for 129 patients. P-53 status was determined immunohistochemically utilizing a commercially available antibody (D07). Clinical endpoints evaluated were overall survival and development of metastases. Results: Twenty-three of the 129 patients had abnormal expression of the P-53 suppressor gene. Presence of this abnormal expression significantly correlated with lower overall survival (p=0.03) and the development of distant metastases (p=0.03). Abnormal expression of the P-53 gene was an independent prognostic indicator when evaluated against clinical stage and Gleason score. Conclusion: This data from patients entered on a phase III multi-institutional, randomized clinical trial shows that abnormal P-53 suppressor gene expression as determined immunohistochemically is an independent predictor of poorer survival and the development of distant metastases in patients with locally advanced adenocarcinoma of the prostate treated with radiation therapy with or without pre-radiation therapy androgen ablation

Twenty-Five Years of Gene Therapy for ADA-SCID: From Bubble Babies to an Approved Drug.

Science.gov (United States)

Ferrua, Francesca; Aiuti, Alessandro

2017-11-01

Twenty-five years have passed since first attempts of gene therapy (GT) in children affected by severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) defect, also known by the general public as bubble babies. ADA-SCID is fatal early in life if untreated. Unconditioned hematopoietic stem cell (HSC) transplant from matched sibling donor represents a curative treatment but is available for few patients. Enzyme replacement therapy can be life-saving, but its chronic use has many drawbacks. This review summarizes the history of ADA-SCID GT over the last 25 years, starting from first pioneering studies in the early 1990s using gamma-retroviral vectors, based on multiple infusions of genetically corrected autologous peripheral blood lymphocytes. HSC represented the ideal target for gene correction to guarantee production of engineered multi-lineage progeny, but it required a decade to achieve therapeutic benefit with this approach. Introduction of low-intensity conditioning represented a crucial step in achieving stable gene-corrected HSC engraftment and therapeutic levels of ADA-expressing cells. Recent clinical trials demonstrated that gamma-retroviral GT for ADA-SCID has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions in patients >13 years after treatment. No abnormal clonal proliferation or leukemia development have been observed in >40 patients treated experimentally in five different centers worldwide. In 2016, the medicinal product Strimvelis™ received marketing approval in Europe for patients affected by ADA-SCID without a suitable human leukocyte antigen-matched related donor. Positive safety and efficacy results have been obtained in GT clinical trials using lentiviral vectors encoding ADA. The results obtained in last 25 years in ADA-SCID GT development fundamentally contributed to improve patients' prognosis, together with earlier diagnosis thanks to newborn screening. These advances

Development of a manualized protocol of massage therapy for clinical trials in osteoarthritis

Directory of Open Access Journals (Sweden)

Ali Ather

2012-10-01

Full Text Available Abstract Background Clinical trial design of manual therapies may be especially challenging as techniques are often individualized and practitioner-dependent. This paper describes our methods in creating a standardized Swedish massage protocol tailored to subjects with osteoarthritis of the knee while respectful of the individualized nature of massage therapy, as well as implementation of this protocol in two randomized clinical trials. Methods The manualization process involved a collaborative process between methodologic and clinical experts, with the explicit goals of creating a reproducible semi-structured protocol for massage therapy, while allowing some latitude for therapists’ clinical judgment and maintaining consistency with a prior pilot study. Results The manualized protocol addressed identical specified body regions with distinct 30- and 60-min protocols, using standard Swedish strokes. Each protocol specifies the time allocated to each body region. The manualized 30- and 60-min protocols were implemented in a dual-site 24-week randomized dose-finding trial in patients with osteoarthritis of the knee, and is currently being implemented in a three-site 52-week efficacy trial of manualized Swedish massage therapy. In the dose-finding study, therapists adhered to the protocols and significant treatment effects were demonstrated. Conclusions The massage protocol was manualized, using standard techniques, and made flexible for individual practitioner and subject needs. The protocol has been applied in two randomized clinical trials. This manualized Swedish massage protocol has real-world utility and can be readily utilized both in the research and clinical settings. Trial registration Clinicaltrials.gov NCT00970008 (18 August 2009

Current status and developments in gene therapy for thalassemia and sickle cell disease

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Evangelia Yannaki

2014-12-01

Full Text Available β-thalassemias and sickle cell anemia (SCA are the most common monogenic diseases worldwide for which curative treatments remain a desired goal. Allogeneic hematopoietic stem cell transplantation (allo-HCT, - the only curative treatment currently available for hemoglobinopaties-, has a narrow application window whereas it incurs several immunological risks. Gene therapy (GT, that is the autologous transplantation of genetically modified hematopoietic stem cells (CD34+, represents a promising new therapeutic strategy which is anticipated to reestablish effective hemoglobin production and render patients transfusion- and drug- independent without the immunological complications that normally accompany allo-HCT. Prior to the application of GT for hemoglobinopathies in the clinic, many years of extensive preclinical research were spent for the optimization of the gene transfer tools and conditions. To date, three GT clinical trials for β-thalassemia and sickle cell disease (SCD have been conducted or are in progress and 3 cases of transfusion independence in thalassemic β0/βΕ patients have been reported. In the present review, the prerequisites for successful implementation of GT, the tough pathway of GT for hemoglobinopathies towards the clinic and the knowledge gained from the first clinical trials as well as the remaining questions and challenges, will be discussed. Overall, after decades of research including achievements but pitfalls as well, the path to GT of human patients with hemoglobinopathies is currently open and highly promising...

From mutation identification to therapy: discovery and origins of the first approved gene therapy in the Western world

NARCIS (Netherlands)

Kastelein, John J. P.; Ross, Colin J. D.; Hayden, Michael R.

2013-01-01

On November 2, 2012, Glybera® (alipogene tipovarvec) was the first human gene therapy to receive long awaited market approval in the Western world. This important milestone is expected to open the door to additional gene therapies for the treatment of many diseases in the future. The development of

Cellular Therapies Clinical Research Roadmap: lessons learned on how to move a cellular therapy into a clinical trial.

Science.gov (United States)

Ouseph, Stacy; Tappitake, Darah; Armant, Myriam; Wesselschmidt, Robin; Derecho, Ivy; Draxler, Rebecca; Wood, Deborah; Centanni, John M

2015-04-01

A clinical research roadmap has been developed as a resource for researchers to identify critical areas and potential pitfalls when transitioning a cellular therapy product from the research laboratory, by means of an Investigational New Drug (IND) application, into early-phase clinical trials. The roadmap describes four key areas: basic and preclinical research, resource development, translational research and Good Manufacturing Practice (GMP) and IND assembly and submission. Basic and preclinical research identifies a new therapeutic concept and demonstrates its potential value with the use of a model of the relevant disease. During resource development, the appropriate specialists and the required expertise to bring this product into the clinic are identified (eg, researchers, regulatory specialists, GMP manufacturing staff, clinicians and clinical trials staff, etc). Additionally, the funds required to achieve this goal (or a plan to procure them) are identified. In the next phase, the plan to translate the research product into a clinical-grade therapeutic is developed. Finally regulatory approval to start the trial must be obtained. In the United States, this is done by filing an IND application with the Food and Drug Administration. The National Heart, Lung and Blood Institute-funded Production Assistance for Cellular Therapies program has facilitated the transition of a variety of cellular therapy products from the laboratory into Phase1/2 trials. The five Production Assistance for Cellular Therapies facilities have assisted investigators by performing translational studies and GMP manufacturing to ensure that cellular products met release specifications and were manufactured safely, reproducibly and at the appropriate scale. The roadmap resulting from this experience is the focus of this article. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Antipyretic therapy in critically ill patients with established sepsis: a trial sequential analysis.

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Zhongheng Zhang

Full Text Available antipyretic therapy for patients with sepsis has long been debated. The present study aimed to explore the beneficial effect of antipyretic therapy for ICU patients with sepsis.systematic review and trial sequential analysis of randomized controlled trials.Pubmed, Scopus, EBSCO and EMBASE were searched from inception to August 5, 2014.Mortality was dichotomized as binary outcome variable and odds ratio (OR was chosen to be the summary statistic. Pooled OR was calculated by using DerSimonian and Laird method. Statistical heterogeneity was assessed by using the statistic I2. Trial sequential analysis was performed to account for the small number of trials and patients.A total of 6 randomized controlled trials including 819 patients were included into final analysis. Overall, there was no beneficial effect of antipyretic therapy on mortality risk in patients with established sepsis (OR: 1.02, 95% CI: 0.50-2.05. The required information size (IS was 2582 and our analysis has not yet reached half of the IS. The Z-curve did not cross the O'Brien-Fleming α-spending boundary or reach the futility, indicating that the non-significant result was probably due to lack of statistical power.our study fails to identify any beneficial effect of antipyretic therapy on ICU patients with established diagnosis of sepsis. Due to limited number of total participants, more studies are needed to make a conclusive and reliable analysis.

77 FR 71194 - Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy...

Science.gov (United States)

2012-11-29

...] Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy... Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products,'' dated November... Evaluation (CBER), Office of Cellular, Tissue, and Gene Therapies (OCTGT). The product areas covered by this...

Clinical infection control in gene therapy : A multidisciplinary conference

NARCIS (Netherlands)

Evans, ME; Jordan, CT; Chang, SMW; Conrad, C; Gerberding, JL; Kaufman, HL; Mayhall, CG; Nolta, JA; Pilaro, AM; Sullivan, S; Weber, DJ; Wivel, NA

2000-01-01

Gene therapy is being studied for the treatment of a variety of acquired and inherited disorders. Retroviruses, adenoviruses, poxviruses, adeno-associated viruses, herpesviruses, and others are being engineered to transfer genes into humans. Treatment protocols using recombinant viruses are being

Effects of traditional Japanese massage therapy on gene expression: preliminary study.

Science.gov (United States)

Donoyama, Nozomi; Ohkoshi, Norio

2011-06-01

Changes in gene expression after traditional Japanese massage therapy were investigated to clarify the mechanisms of the clinical effects of traditional Japanese massage therapy. This was a pilot experimental study. The study was conducted in a laboratory at Tsukuba University of Technology. The subjects were 2 healthy female volunteers (58-year-old Participant A, 55-year-old Participant B). The intervention consisted of a 40-minute full-body massage using standard traditional Japanese massage techniques through the clothing and a 40-minute rest as a control, in which participants lie on the massage table without being massaged. Before and after an intervention, blood was taken and analyzed by microarray: (1) The number of genes whose expression was more than double after the intervention than before was examined; (2) For those genes, gene ontology analysis identified statistically significant gene ontology terms. The gene expression count in the total of 41,000 genes was 1256 genes for Participant A and 1778 for Participant B after traditional Japanese massage, and was 157 and 82 after the control, respectively. The significant gene ontology terms selected by both Participants A and B after massage were "immune response" and "immune system," whereas no gene ontology terms were selected by them in the control. It is implied that traditional Japanese massage therapy may affect the immune function. Further studies with more samples are necessary.

Gene therapy decreases seizures in a model of Incontinentia pigmenti.

Science.gov (United States)

Dogbevia, Godwin K; Töllner, Kathrin; Körbelin, Jakob; Bröer, Sonja; Ridder, Dirk A; Grasshoff, Hanna; Brandt, Claudia; Wenzel, Jan; Straub, Beate K; Trepel, Martin; Löscher, Wolfgang; Schwaninger, Markus

2017-07-01

Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104. © 2017 American Neurological Association.

Mesenchymal stromal cells retrovirally transduced with prodrug-converting genes are suitable vehicles for cancer gene therapy.

Science.gov (United States)

Ďuriniková, E; Kučerová, L; Matúšková, M

2014-01-01

Mesenchymal stem/stromal cells (MSC) possess a set of several fairly unique properties which make them ideally suitable both for cellular therapies and regenerative medicine. These include: relative ease of isolation, the ability to differentiate along mesenchymal and non-mesenchymal lineages in vitro and the ability to be extensively expanded in culture without a loss of differentiative capacity. MSC are not only hypoimmunogenic, but they mediate immunosuppression upon transplantation, and possess pronounced anti-inflammatory properties. They are able to home to damaged tissues, tumors, and metastases following systemic administration. The ability of homing holds big promise for tumor-targeted delivery of therapeutic agents. Viruses are naturally evolved vehicles efficiently transferring their genes into host cells. This ability made them suitable for engineering vector systems for the delivery of genes of interest. MSC can be retrovirally transduced with genes encoding prodrug-converting genes (suicide genes), which are not toxic per se, but catalyze the formation of highly toxic metabolites following the application of a nontoxic prodrug. The homing ability of MSC holds advantages compared to virus vehicles which display many shortcomings in effective delivery of the therapeutic agents. Gene therapies mediated by viruses are limited by their restricted ability to track cancer cells infiltrating into the surrounding tissue, and by their low migratory capacity towards tumor. Thus combination of cellular therapy and gene delivery is an attractive option - it protects the vector from immune surveillance, and supports targeted delivery of a therapeutic gene/protein to the tumor site.

Gene Editing and CRISPR Therapeutics: Strategies Taught by Cell and Gene Therapy.

Science.gov (United States)

Ramirez, Juan C

2017-01-01

A few years ago, we assisted in the demonstration for the first time of the revolutionary idea of a type of adaptive-immune system in the bacteria kingdom. This system, named CRISPR, and variants engineered in the lab, have been demonstrated as functional with extremely high frequency and fidelity in almost all eukaryotic cells studied to date. The capabilities of this RNA-guided nuclease have added to the interest that was announced with the advent of previous technologies for genome editing tools, such as ZFN and TALEN. The capabilities exhibited by these gene editors, opens up a novel scenario that indicates the promise of a next-generation medicine based on precision and personalized objectives, mostly due to the change in the paradigm regarding gene-surgery. This has certainly attracted, like never before, the attention of the biotech business and investor community. This chapter offers a brief overview of some of the factors that have contributed to a rapid entry into the biotech and pharmaceutical company's pipeline, focusing on how cell and gene therapies (CGT), collectively known as advanced therapies, have become the driving forces toward the therapeutic uses of gene editing technology. The sum of all those efforts for more than 30years has contributed to the new paradigm of considering genes as medicines. Copyright © 2017. Published by Elsevier Inc.

Modified T-cells (using TCR and CTAs, chimeric antigen receptor (CAR and other molecular tools in recent gene therapy

Directory of Open Access Journals (Sweden)

A.S. Odiba

2018-07-01

Full Text Available T-cell-based cancer immunotherapy by the transfer of cloned TCRs that are isolated from tumor penetrating T-cells becomes a possibility through NY-ESOc259; a human-derived affinity-enhanced TCR that provides a level of sufficiency in long-term safety and efficacy. NY-ESOc259 recognizes a peptide common to CTAs (LAGE-1 and NY-ESO-1 in melanoma. Risks associated with insertion related transformation in gene therapy have been alleviated through strategies that include the engineering of transcription activator like effector nucleases (TALEN, RNA-guided nucleases (CRISPR/Cas9, Zinc-finger nucleases (ZFN. Cancer immunotherapy based on the genetic modification of autologous T-cells (dependent on the engineered autologous CD8+ T-cells, designed to distinguish and destroy cells bearing tumor-specific antigens via a CAR is able to exterminate B-cell leukemias and lymphomas that are resilient to conventional therapies. A tool with a very large reservoir of potentials in molecular therapy strategy is the Pluripotent Stem Cells (PSC, with pluripotency factors that include Klf4, Sox2, c-Myc, Oct4, differentiating into disease-associated cell phenotypes of three germ layers, comprising of mesoderm (e.g. cardiac cells, blood and muscle, endoderm (liver, pancreas and ectoderm (epidermis, neurons. It finds good application in disease modelling as well as therapeutic options in the restoration of CGD by using AAVS1 as the vector where the therapeutic cassette is integrated into the locus to restore superoxide production in the granulocytes. Fascinatingly, Clinical trial involving iPSC are already underway where scientists have plans to use iPSC-derived cells to treat macular degeneration (a devastating age-related eye disease. Application of these findings has redefined incurable diseases disorders as curable. Keywords: Clinical trials, Disorders, Gene therapy, Molecular biology, Pharmacotherapy, Vector

The hopes and fears of in utero gene therapy for genetic disease--a review.

Science.gov (United States)

Coutelle, C; Themis, M; Waddington, S; Gregory, L; Nivsarkar, M; Buckley, S; Cook, T; Rodeck, C; Peebles, D; David, A

2003-10-01

Somatic gene delivery in utero is a novel approach to gene therapy for genetic disease. It is based on the concept that application of gene therapy vectors to the fetus in utero may prevent the development of early disease related tissue damage, may allow targeting of otherwise inaccessible organs, tissues and still expanding stem cell populations and may also provide postnatal tolerance against the therapeutic transgenic protein. This review outlines the hypothesis and scientific background of in utero gene therapy and addresses some of the frequently expressed concerns raised by this still experimental, potentially preventive gene therapy approach. We describe and discuss the choice of vectors, of animal models and routes of administration to the fetus. We address potential risk factors of prenatal gene therapy such as vector toxicity, inadvertent germ line modification, developmental aberration and oncogenesis as well as specific risks of this procedure for the fetus and mother and discuss their ethical implications.

Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

Science.gov (United States)

Lin, Yi-Chu; Wang, Po-Yu; Tsai, Shih-Chih; Lin, Chien-Liang; Tai, Hsuen-Yung; Lo, Chi-Fang; Wu, Shiow-Ing; Chiang, Yu-Mei; Liu, Li-Ling

2015-01-01

Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.

Specifically targeted gene therapy for small-cell lung cancer

DEFF Research Database (Denmark)

Christensen, C.L.; Zandi, R.; Gjetting, T.

2009-01-01

Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous...

Childhood asthma clusters and response to therapy in clinical trials.

Science.gov (United States)

Chang, Timothy S; Lemanske, Robert F; Mauger, David T; Fitzpatrick, Anne M; Sorkness, Christine A; Szefler, Stanley J; Gangnon, Ronald E; Page, C David; Jackson, Daniel J

2014-02-01

Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

Combinatorial RNA-based gene therapy for the treatment of HIV/AIDS.

Science.gov (United States)

Chung, Janet; DiGiusto, David L; Rossi, John J

2013-03-01

HIV/AIDS continues to be a worldwide health problem and viral eradication has been an elusive goal. HIV+ patients are currently treated with combination antiretroviral therapy (cART) which is not curative. For many patients, cART is inaccessible, intolerable or unaffordable. Therefore, a new class of therapeutics for HIV is required to overcome these limitations. Cell and gene therapy for HIV has been proposed as a way to provide a functional cure for HIV in the form of a virus/infection resistant immune system. In this review, the authors describe the standard therapy for HIV/AIDS, its limitations, current areas of investigation and the potential of hematopoietic stem cells modified with anti-HIV RNAs as a means to affect a functional cure for HIV. Cell and gene therapy for HIV/AIDS is a promising alternative to antiviral drug therapy and may provide a functional cure. In order to show clinical benefit, multiple mechanisms of inhibition of HIV entry and lifecycle are likely to be required. Among the most promising antiviral strategies is the use of transgenic RNA molecules that provide protection from HIV infection. When these molecules are delivered as gene-modified hematopoietic stem and progenitor cells, long-term repopulation of the patient's immune system with gene-modified progeny has been observed.

76 FR 9028 - Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability

Science.gov (United States)

2011-02-16

...] Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products; Availability AGENCY: Food and... Therapy Products'' dated January 2011. The guidance document provides manufacturers of cellular and gene... for Industry: Potency Tests for Cellular and Gene Therapy Products'' dated January 2011. The guidance...

Nanoparticle-mediated delivery of suicide genes in cancer therapy.

Science.gov (United States)

Vago, Riccardo; Collico, Veronica; Zuppone, Stefania; Prosperi, Davide; Colombo, Miriam

2016-09-01

Conventional chemotherapeutics have been employed in cancer treatment for decades due to their efficacy in killing the malignant cells, but the other side of the coin showed off-target effects, onset of drug resistance and recurrences. To overcome these limitations, different approaches have been investigated and suicide gene therapy has emerged as a promising alternative. This approach consists in the introduction of genetic materials into cancerous cells or the surrounding tissue to cause cell death or retard the growth of the tumor mass. Despite promising results obtained both in vitro and in vivo, this innovative approach has been limited, for long time, to the treatment of localized tumors, due to the suboptimal efficiency in introducing suicide genes into cancer cells. Nanoparticles represent a valuable non-viral delivery system to protect drugs in the bloodstream, to improve biodistribution, and to limit side effects by achieving target selectivity through surface ligands. In this scenario, the real potential of suicide genes can be translated into clinically viable treatments for patients. In the present review, we summarize the recent advances of inorganic nanoparticles as non-viral vectors in terms of therapeutic efficacy, targeting capacity and safety issues. We describe the main suicide genes currently used in therapy, with particular emphasis on toxin-encoding genes of bacterial and plant origin. In addition, we discuss the relevance of molecular targeting and tumor-restricted expression to improve treatment specificity to cancer tissue. Finally, we analyze the main clinical applications, limitations and future perspectives of suicide gene therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gene Therapy in Cardiac Arrhythmias

Directory of Open Access Journals (Sweden)

Praveen S.V

2006-04-01

Full Text Available 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 node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger.Lastly the ethical concerns need to be addressed.

Recruitment of Participants to a Clinical Trial of Botanical Therapy for Benign Prostatic Hyperplasia

Science.gov (United States)

Foster, Harris E.; McVary, Kevin T.; Meleth, Sreelatha; Stavris, Karen; Downey, Joe; Kusek, John W.

2011-01-01

Abstract Objectives The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. Design CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. Subjects The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. Results The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. Conclusions Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated

Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia.

Science.gov (United States)

Lee, Jeannette Y; Foster, Harris E; McVary, Kevin T; Meleth, Sreelatha; Stavris, Karen; Downey, Joe; Kusek, John W

2011-05-01

The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated study population.

Utilizing social media to study information-seeking and ethical issues in gene therapy.

Science.gov (United States)

Robillard, Julie M; Whiteley, Louise; Johnson, Thomas Wade; Lim, Jonathan; Wasserman, Wyeth W; Illes, Judy

2013-03-04

The field of gene therapy is rapidly evolving, and while hopes of treating disorders of the central nervous system and ethical concerns have been articulated within the academic community, little is known about views and opinions of different stakeholder groups. To address this gap, we utilized social media to investigate the kind of information public users are seeking about gene therapy and the hopes, concerns, and attitudes they express. We conducted a content analysis of questions containing the keywords "gene therapy" from the Q&A site "Yahoo! Answers" for the 5-year period between 2006 and 2010. From the pool of questions retrieved (N=903), we identified those containing at least one theme related to ethics, environment, economics, law, or society (n=173) and then characterized the content of relevant answers (n=399) through emergent coding. The results show that users seek a wide range of information regarding gene therapy, with requests for scientific information and ethical issues at the forefront of enquiry. The question sample reveals high expectations for gene therapy that range from cures for genetic and nongenetic diseases to pre- and postnatal enhancement of physiological attributes. Ethics questions are commonly expressed as fears about the impact of gene therapy on self and society. The answer sample echoes these concerns but further suggests that the acceptability of gene therapy varies depending on the specific application. Overall, the findings highlight the powerful role of social media as a rich resource for research into attitudes toward biomedicine and as a platform for knowledge exchange and public engagement for topics relating to health and disease.

Anti-Angiogenic Gene Therapy for Prostate Cancer

Science.gov (United States)

2004-04-01

S. Parvovirus vectors for cancer gene therapy. Expert. Opin. Bid. Ther., 2004, 4: 53-64. Ponnazhagan, S., and Hoover, F. Delivery of DNA to tumor... vaccine with plasmid adjuvants 95h Annual Meeting of the American Society for Cancer Research, Orlando, FL, April 2004. Chaudhuri, T.R., Cao, Z...with recombinant AAV vectors results in sustained expression in a dog model of hemophilia. Gene Ther., 5: 40-49, 1998. 2ś 35. Bohl, D., Bosch, A

p53 as the focus of gene therapy: past, present and future.

Science.gov (United States)

Valente, Joana Fa; Queiroz, Joao A; Sousa, Fani

2018-01-15

Several gene deviations can be responsible for triggering oncogenic processes. However, mutations in tumour suppressor genes are usually more associated to malignant diseases, being p53 one of the most affected and studied element. p53 is implicated in a number of known cellular functions, including DNA damage repair, cell cycle arrest in G1/S and G2/M and apoptosis, being an interesting target for cancer treatment. Considering these facts, the development of gene therapy approaches focused on p53 expression and regulation seems to be a promising strategy for cancer therapy. Several studies have shown that transfection of cancer cells with wild-type p53 expressing plasmids could directly drive cells into apoptosis and/or growth arrest, suggesting that a gene therapy approach for cancer treatment can be based on the re-establishment of the normal p53 expression levels and function. Up until now, several clinical research studies using viral and non-viral vectors delivering p53 genes, isolated or combined with other therapeutic agents, have been accomplished and there are already in the market therapies based on the use of this gene. This review summarizes the different methods used to deliver and/or target the p53 as well as the main results of therapeutic effect obtained with the different strategies applied. Finally, the ongoing approaches are described, also focusing the combinatorial therapeutics to show the increased therapeutic potential of combining gene therapy vectors with chemo or radiotherapy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Advances in gene therapy and early imaging monitoring for avascular necrosis of the femoral head

International Nuclear Information System (INIS)

Wang Peng; Lan Xiaoli; Zhang Yongxue; Qi Hongyan

2012-01-01

Gene therapy is a method that transfers foreign gene to target cells, so as to correct or compensate the disease which is caused by the gene defects and abnormalities. As a new technology, gene therapy has been used in many fields, such as cancer, cardiovascular and nervous system disease, and it brings some hope for patients with difficult and complicated disease. Avascular necrosis of femoral head is a refractory and common disease in clinical, but the traditional surgery therapy and conservative treatment both have many shortcomings,and the effect is unsatisfactory. As a new technology,gene therapy showed bright future in orthopedics ischemic disease, and its potential feasibility has been confirmed by many animal experiments. This article focuses on the research progress of gene therapy and early monitoring in the avascular necrosis of the femoral head. (authors)

The TOPSHOCK study: Effectiveness of radial shockwave therapy compared to focused shockwave therapy for treating patellar tendinopath - design of a randomised controlled trial

Directory of Open Access Journals (Sweden)

Diercks Ron L

2011-10-01

Full Text Available Abstract Background Patellar tendinopathy is a chronic overuse injury of the patellar tendon that is especially prevalent in people who are involved in jumping activities. Extracorporeal Shockwave Therapy is a relatively new treatment modality for tendinopathies. It seems to be a safe and promising part of the rehabilitation program for patellar tendinopathy. Extracorporeal Shockwave Therapy originally used focused shockwaves. Several years ago a new kind of shockwave therapy was introduced: radial shockwave therapy. Studies that investigate the effectiveness of radial shockwave therapy as treatment for patellar tendinopathy are scarce. Therefore the aim of this study is to compare the effectiveness of focussed shockwave therapy and radial shockwave therapy as treatments for patellar tendinopathy. Methods/design The TOPSHOCK study (Tendinopathy Of Patella SHOCKwave is a two-armed randomised controlled trial in which the effectiveness of focussed shockwave therapy and radial shockwave therapy are directly compared. Outcome assessors and patients are blinded as to which treatment is given. Patients undergo three sessions of either focused shockwave therapy or radial shockwave therapy at 1-week intervals, both in combination with eccentric decline squat training. Follow-up measurements are scheduled just before treatments 2 and 3, and 1, 4, 7 and 12 weeks after the final treatment. The main outcome measure is the Dutch VISA-P questionnaire, which asks for pain, function and sports participation in subjects with patellar tendinopathy. Secondary outcome measures are pain determined with a VAS during ADL, sports and decline squats, rating of subjective improvement and overall satisfaction with the treatment. Patients will also record their sports activities, pain during and after these activities, and concurrent medical treatment on a weekly basis in a web-based diary. Results will be analysed according to the intention-to-treat principle. Discussion

A randomised controlled trial evaluating family mediated exercise (FAME therapy following stroke

Directory of Open Access Journals (Sweden)

Stokes Emma

2008-06-01

Full Text Available Abstract Background Stroke is a leading cause of disability among adults worldwide. Evidence suggests that increased duration of exercise therapy following stroke has a positive impact on functional outcome following stroke. The main objective of this randomised controlled trial is to evaluate the impact of additional family assisted exercise therapy in people with acute stroke. Methods/Design A prospective multi-centre single blind randomised controlled trial will be conducted. Forty patients with acute stroke will be randomised into either an experimental or control group. The experimental group will receive routine therapy and additional lower limb exercise therapy in the form of family assisted exercises. The control group will receive routine therapy with no additional formal input from their family members. Participants will be assessed at baseline, post intervention and followed up at three months using a series of standardised outcome measures. A secondary aim of the project is to evaluate the impact of the family mediated exercise programme on the person with stroke and the individual(s assisting in the delivery of exercises using a qualitative methodology. The study has gained ethical approval from the Research Ethics Committees of each of the clinical sites involved in the study. Discussion This study will evaluate a structured programme of exercises that can be delivered to people with stroke by their 'family members/friends'. Given that the progressive increase in the population of older people is likely to lead to an increased prevalence of stroke in the future, it is important to reduce the burden of this illness on the individual, the family and society. Family mediated exercises can maximise the carry over outside formal physiotherapy sessions, giving patients the opportunity for informal practice. Trial Registration The protocol for this study is registered with the US NIH Clinical trials registry (NCT00666744