AAV vectors have emerged as a promising delivery system for gene therapy of numerous muscular dystrophies. Systemic delivery protocols have been developed in mice that lead to whole body amelioration of the pathophysiology, suggesting that this approach could lead to an effective therapy. Most studies have been performed in models for recessively inherited disorders such as DMD, but related approaches have begun to be adapted for dominantly inherited disorder such as FSHD. However, many obstacles remain before whole body treatment via AAV can be achieved in humans. These include developing robust and safe methods for wide spread targeting of critical muscle groups including limb, respiratory and cardiac muscles. Critical to these goals is a need for gene regulatory cassettes that can direct high-level gene expression in all skeletal muscle fiber types and anatomical muscles, but not in non-muscle cells including immune effector cells. A further need is to expand the utility of these approaches by developing vectors that can safely and efficiently knock-down mutant gene products in dominantly inherited dystrophies. This project is a collaborative effort among a diverse and highly experienced group of scientists with extensive expertise in the study of muscle biology, muscular dystrophy, gene expression, RNAi and gene therapy. We propose to adapt methods for AAV-mediated gene transfer to large animal models for DMD by focusing on expression cassette design, AAV serotype comparisons, delivery methods and scale-up to test the hypothesis that AAV vectors can be used to target all the major muscle groups of the body. In parallel, we will adapt AAV systems for targeting and studying the dominant disorder FSHD, using cell lines and mouse models. Together these studies could lead to human clinical trials for DMD using regional limb, diaphragm and cardiac delivery of AAV vectors, and will bring gene therapy for dominant disorders closer to pre-clinical testing. One clinical trial involving IM injection of AAV for DMD is already planned at Seattle Children's Hospital, and together with the clinical trials infrastructure development in Project 2 these studies could lead to increased clinical interventions for both dominantly and recessively inherited muscular dystrophies.models. Together these studies could lead to human clinical trials for DMD using regional limb, diaphragm and cardiac delivery of AAV vectors, and will bring gene therapy for dominant disorders closer to pre-clinical testing. One clinical trial involving IM injection of AAV for DMD is already planned at Seattle Children's Hospital, and together with the clinical trials infrastructure development in Project 2 these studies could lead to increased clinical interventions for both dominantly and recessively inherited muscular dystrophies. DMD and FSHD are the 2 most common muscular dystrophies and are collectively among the most common monogenic inherited disorders. There are no cures, and therapeutic interventions are minimal. Consequently patients often have significantly reduced lifespans, impaired mobility and quality of life. This proposal is to develop therapies addressing the primary cause of these disorders. These pre-clinical studies are designed to nrenare the research for human clinical trials of gene theranv
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