This application requests support for the third cycle of this program project that has been dedicated to the development of gene therapy for cardiovascular diseases. We plan in this cycle to focus on the pre-clinical development of gene therapy to liver for the treatment of two severe dyslipidemias: familial hypercholesterolemia (FH) and abetalipoproteinemia (ABL). In studies performed during the current cycle of this grant we developed a number of vectors based on novel adeno-associated viruses (AAV). We showed that many of these have substantially improved performance profiles in terms of gene transfer efficiency, safety and immunogenicity. The goal of this application is to identify the optimal AAV vector for liver directed gene therapy and to study areas of vector biology relevant for the potential testing of these vectors in humans. The feasibility of treating FH and ABL will be assessed in relevant animal models. Key milestones are identification of the clinical candidate vector in year one and the development of sufficient pre-clinical data at the end of year 5 to proceed with phase I clinical trials in both FH and/or ABL in a subsequent application. Project I, directed by Dr. J. Wilson, will develop the clinical candidate vector and will evaluate key issues of vector immunology relevant to safety and efficacy. Project II, directed by Dr. D. Rader, will perform all pre-clincal studies of gene therapy in animals models of FH (mice, rabbits and monkeys) and ABL (mice). Project III, directed by Dr. G. Gao, will evaluate the molecular biology of AAV in liver in terms of recombination with endogenous virus, integration and oncogenicity. The Projects will be supported by three scientific cores - Vector (Core A), Cell Morphology (Core B), and Animal Models (Core C) - and the Administrative Core (Core D). Lay abstract. This project will use a novel viral vector system based on adeno-associated viral vectors (AAV) to develop gene therapy for two very severe inherited forms of lipid metabolism called: familial hypercholesterolemia (FH) and abetalipoproteinemia (ABL). The grant will do all pre-clinical studies necessary to begin clinical trials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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Mcdonald, Cheryl
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University of Pennsylvania
Schools of Medicine
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