Effective treatment for Duchenne muscular dystrophy depends on replacement of dystrophin in skeletal muscle (and other tissues) with protein of sufficient quality and quantity to prevent the disease manifestations. The objective of this project is to test dystrophin replacement in transgenic mdx mice, where problems of vector capacity, immunogenicity, and delivery are obviated by germline transmission of the dystrophin transgene. We plan to use this system to determine the minimum expression levels and the minimum structural requirements of the dystrophin protein needed to correct the dystrophic phenotype. We will produce transgenic mice with full length dystsrophin cDNA under the control of a series of promoters designed to give expression either systemically or specifically in skeletal and cardiac muscle or the central nervous system. We also will produce transgenic mice with different versions of the dystrophin cDNA, including """"""""minidystrophin"""""""" and other constructs with different deletions of the central rod domain. Dystrophin expression will determined in the transgenic mice by immunohistochemistry and western blot analysis. The transgenic mice will then be bred with mdx mice, and the effects of the dystrophin transgene on muscle histochemistry and stretch-induced muscle injury will be assessed. We expect that this project will identify the best dystrophin constructs for use in experimental gene therapy in mdx mice, and eventually in patients with Duchenne muscular dystrophy.
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