The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Ronald G. Crystal - One of the best experts on this subject based on the ideXlab platform.
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intrapleural Gene Therapy for alpha 1 antitrypsin deficiency related lung disease
Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation, 2018Co-Authors: Katie M Stiles, Dolan Sondhi, Stephen M Kaminsky, Jonathan B Rosenberg, Ronald G. CrystalAbstract:Alpha-1 antitrypsin deficiency (AATD) manifests primarily as early-onset emphysema caused by the destruction of the lung by neutrophil elastase due to low amounts of the serine protease inhibitor alpha-1 antitrypsin (AAT). The current Therapy involves weekly intravenous infusions of AAT-derived from pooled human plasma that is efficacious, yet costly. Gene Therapy applications designed to provide constant levels of the AAT protein are currently under development. The challenge is for Gene Therapy to provide sufficient amounts of AAT to normalize the inhibitor level and anti-neutrophil elastase capacity in the lung. One strategy involves administration of an adeno-associated virus (AAV) Gene Therapy vector to the pleural space providing both local and systemic production of AAT to reach consistent therapeutic levels. This review focuses on the strategy, advantages, challenges, and updates for intrapleural administration of Gene Therapy vectors for the treatment of AATD.
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Gene Therapy for metachromatic leukodystrophy
Journal of Neuroscience Research, 2016Co-Authors: Jonathan B Rosenberg, Ronald G. Crystal, Stephen M Kaminsky, Patrick Aubourg, Dolan SondhiAbstract:Leukodystrophies (LDs) are rare, often devastating Genetic disorders with neurologic symptoms. There are currently no disease-specific therapeutic approaches for these diseases. In this review we use metachromatic leukodystrophy as an example to outline in the brief the therapeutic approaches to MLD that have been tested in animal models and in clinical trials, such as enzyme-replacement Therapy, bone marrow/umbilical cord blood transplants, ex vivo transplantation of Genetically modified hematopoietic stem cells, and Gene Therapy. These studies suggest that to be successful the ideal Therapy for MLD must provide persistent and high level expression of the deficient Gene, arylsulfatase A in the CNS. Gene Therapy using adeno-associated viruses is therefore the ideal choice for clinical development as it provides the best balance of potential for efficacy with reduced safety risk. Here we have summarized the published preclinical data from our group and from others that support the use of a Gene Therapy with AAVrh.10 serotype for clinical development as a treatment for MLD, and as an example of the potential of Gene Therapy for LDs especially for Krabbe disease, which is the focus of this special issue. © 2016 Wiley Periodicals, Inc.
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Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease.
Annals of the American Thoracic Society, 2016Co-Authors: Maria J. Chiuchiolo, Ronald G. CrystalAbstract:Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation Therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, Gene Therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT Gene Therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT Gene Therapy to the bedside.
Charles Coutelle - One of the best experts on this subject based on the ideXlab platform.
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On the scientific and ethical issues of fetal somatic Gene Therapy
Gene Therapy, 2002Co-Authors: Charles Coutelle, C RodeckAbstract: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.
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fetal somatic Gene Therapy
Molecular Human Reproduction, 1996Co-Authors: A M Douar, M Themis, Charles CoutelleAbstract:Fetal somatic Gene Therapy is emerging as a new experimental approach, in particular to prevent irreversible perinatal disease manifestation for many inherited conditions. Early therapeutic Gene application may also allow targeting of still expanding stem cell populations of organ or cell systems inaccessible later in life and help to avoid immune sensitization against the therapeutic vector system or transGene protein product. The progress in development of ultrasound scanning and embryofetoscopy over the last decade has made minimally invasive administration of therapeutic Gene transfer vectors to the fetus in utero possible in principle. We review here the different considerations in choosing candidate diseases, the possible routes of administration and times in fetal development for application of a therapeutic Gene and discuss the benefits and problems of present vector systems in this context. Given the many unknown aspects of fetal Gene transfer, it is essential to extensively investigate this new approach to Gene Therapy in animal models for specific diseases, to improve on the technology of delivery and to assess efficacy of expression as well as the possible side effects before application to humans can be considered.
Valder R Arruda - One of the best experts on this subject based on the ideXlab platform.
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protein engineered coagulation factors for hemophilia Gene Therapy
Molecular therapy. Methods & clinical development, 2019Co-Authors: Benjamin J Samelsonjones, Valder R ArrudaAbstract:Hemophilia A (HA) and hemophilia B (HB) are X-linked bleeding disorders due to inheritable deficiencies in either coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Recently, Gene Therapy clinical trials with adeno-associated virus (AAV) vectors and protein-engineered transGenes, B-domain deleted (BDD) FVIII and FIX-Padua, have reported near-phenotypic cures in subjects with HA and HB, respectively. Here, we review the biology and the clinical development of FVIII-BDD and FIX-Padua as transGenes. We also examine alternative bioengineering strategies for FVIII and FIX, as well as the immunological challenges of these approaches. Other engineered proteins and their potential use in Gene Therapy for hemophilia with inhibitors are also discussed. Continued advancement of Gene Therapy for HA and HB using protein-engineered transGenes has the potential to alleviate the substantial medical and psychosocial burdens of the disease.
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Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy
Elsevier, 2019Co-Authors: Benjamin J. Samelson-jones, Valder R ArrudaAbstract:Hemophilia A (HA) and hemophilia B (HB) are X-linked bleeding disorders due to inheritable deficiencies in either coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Recently, Gene Therapy clinical trials with adeno-associated virus (AAV) vectors and protein-engineered transGenes, B-domain deleted (BDD) FVIII and FIX-Padua, have reported near-phenotypic cures in subjects with HA and HB, respectively. Here, we review the biology and the clinical development of FVIII-BDD and FIX-Padua as transGenes. We also examine alternative bioengineering strategies for FVIII and FIX, as well as the immunological challenges of these approaches. Other engineered proteins and their potential use in Gene Therapy for hemophilia with inhibitors are also discussed. Continued advancement of Gene Therapy for HA and HB using protein-engineered transGenes has the potential to alleviate the substantial medical and psychosocial burdens of the disease. Keywords: Hemophilia A, hemophilia B, Gene Therapy, bioengineering, factor VIII, factor IX, factor IX Padua, B-domain delete factor VIII, immunogenicity, protein engineerin
Fred D Ledley - One of the best experts on this subject based on the ideXlab platform.
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pharmaceutical approach to somatic Gene Therapy
Pharmaceutical Research, 1996Co-Authors: Fred D LedleyAbstract:The pharmaceutical approach to somatic Gene Therapy is based on consideration of a Gene as a chemical entity with specific physical, chemical and colloidal properties. The Genes that are required for Gene Therapy are large molecules (>1 × 106 Daltons, >100 nm diameter) with a net negative charge that prevents diffusion through biological barriers such as an intact endothelium, the plasma membrane or the nuclear membrane. New methods for Gene Therapy are based on increasing knowledge of the pathways by which DNA may be internalized into cells and traffic to the nucleus, pharmaceutical experience with particulate drug delivery systems, and the ability to control Gene expression with recombined Genetic elements. This article reviews two themes in the development of Gene therapies: first, the current approaches involving the administration of cells, viruses and plasmid DNA; second, the emerging pharmaceutical approach to Gene Therapy based on the pharmaceutical characteristics of DNA itself and methods for advanced drug delivery.
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Development in Somatic Gene Therapy
Expert Opinion on Investigational Drugs, 1994Co-Authors: Fred D LedleyAbstract:Clinical trials of Gene transfer have begun to validate the clinical potential of Gene Therapy. With this progress, attention has turned increasingly to analysing the ability of various methods of Gene Therapy to satisfy clinical and commercial needs. There are fundamental differences between cell-based therapies, which employ Genetically modified cells as a therapeutic product, virus-based therapies, which employ recombinant viral vectors as a therapeutic product and Gene-based therapies in which DNA itself is formulated as a pharmaceutical product, in terms of the technologies required to develop and produce the product, the mode of clinical application, the clinical risks and the economics of commercialisation. This report reviews the potential indications for Gene Therapy and the status of various approaches to Gene Therapy in development in the context of a field which is moving rapidly from basic research to product development.
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somatic Gene Therapy in otolaryngology head and neck surgery
Archives of Otolaryngology-head & Neck Surgery, 1993Co-Authors: Bert W Omalley, Fred D LedleyAbstract:The initial clinical trials of somatic Gene Therapy have demonstrated that Gene transfer can be performed safely in a clinical setting and with public acceptance. These trials have focused attention on the broad applications of this technology in routine medical and surgical practice. This article reviews the reasons why somatic Gene Therapy could lead to significant improvements in clinical practice as well as specific therapies in otolaryngology—head and neck surgery. Early applications include the treatment of inherited diseases such as cystic fibrosis, new approaches for treating malignancies, new methods for enhancing tissue repair, and reGeneration after plastic and reconstructive surgery, and the potential for using the thyroid as a target for somatic Gene Therapy. The following review will illustrate how somatic Gene Therapy may have a significant impact not only on the treatment of rare Genetic diseases but on managing the common problems encountered by physicians and patients in daily practice. (Arch Otolaryngol Head Neck Surg. 1993;119:1191-1197)
John J.p. Kastelein - One of the best experts on this subject based on the ideXlab platform.
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Gene Therapy for lipoprotein lipase deficiency.
Current Opinion in Lipidology, 2012Co-Authors: John J.p. KasteleinAbstract:Purpose of reviewThe present review summarizes the clinical development of adeno-associated viral vector (AAV)1-lipoprotein lipase (LPL)S447X Gene Therapy (alipoGene tiparvovec) for lipoprotein lipase deficiency. Lipoprotein lipase deficiency is a rare inherited disease characterized by severe hyper
