Muscular dystrophy is a common genetic disease that affects 1 in 3500 male births annually. The disease is characterized by early muscle hypertrophy followed by muscle degeneration and early death in adolescence resulting from failure of heart and diaphragm muscle. The disease results from mutations that affect expression or function of dystrophin, an important structural component of the subplasma membrane. Currently no treatment is available. The overall goal of the proposed research is to develop gene and cell therapeutic methods for treatment of muscular dystrophy. Clinical, pre-clinical and basic muscle cell development studies are described in which experts in gene transfer, muscle cell biology, animal models of muscular dystrophy and clinical applications are brought together in a manner to achieve the highest level of data sharing, synergy and creative solution finding will be possible. Project 1 (J Mendell) will define clinical end-points and identify cohorts of patient that would participate in a phase I dose escalation safety clinical trial using an AAV gene vector carrying the functional dystrophin minigene delivered to a single skeletal muscle and continue gene therapy clinical trials for limb girdle MD. In Project 2 (X Xiao and J Kornegay), will explore methods for improved AAV-dys gene delivery using the dog model. In Project 3 (J Huard), experiments using muscle stem cells will be carried out using dystrophic mouse models in attempts to achieve muscle delivery of normal muscle derived stem cells to engraft into diseased heart. In Project 4 (J Glorioso), a novel functional genomics approach to identify genes that participate in differentiation of mouse embryonic stem cells toward muscle cell lineages is proposed using HSV gene vector cDNA libraries obtained from muscle derived stem cells. The core programs are designed to directly support the projects in the form of Administration (Core A: J Glorioso and P Robbins), Clinical Vector Production (Core B: J Barranger), a muscular dystrophy dog colony (Core C: J Kornegey) and Imaging (Core D: S Watkins) to provide information on the results of gene transfer in animals and patients. Finally, our center includes a training program for residents interested in gene therapy for muscle disease. We believe this to be a timely and highly innovative proposal which is likely to provide new armroaches to the treatment of muscular dvstrophv.
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