Molecular and Cellular Therapies for Muscular Dystrophy

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Duchenne muscular dystrophy, caused by mutations in the gene encoding dystrophin, is one of the most prevalent and devastating human genetic diseases. The goal of this application is to enhance and improve therapeutic strategies and to develop the basic biology for new innovative approaches. Jeff Chamberlain will build on his expertise in DMD gene therapy by developing novel vectors able to deliver mini-dystrophins and/or myogenic regulatory genes either to muscle cells or via hematopoietic and mesenchymal stem cells. A related goal will be exploring methods for the efficient conversion of somatic stem cells into skeletal muscle. Stan Froehner will study the role of alpha-dystrobrevin, a dystrophin-associated protein, in the degeneration process. Mice lacking alpha-dystrobrevin develop muscular dystrophy through a mechanism that involves alteration in cellular signaling. The key functional domains of alpha-dystrobrevin and proteins that interact with these domains will be identified. alpha-dystrobrevin, modified to target to the membrane, will be tested for its ability to alleviate the dystrophic pathology in mdx muscle. Finally, changes in gene expression induced in muscle cells per se by the absence of alpha-dystrobrevin will be analyzed. Steve Hausehka will test the in vivo tissue specificity and long-term expression of regulatory gene cassettes designed to be optimal for packaging different therapeutic cDNAs into AAV, Lentiviral, and Adenoviral vectors. These vectors will then be used to deliver micro-, mini-, and full-length dystrophin and a variety of compensatory proteins to the dystrophic muscles of mdx4cv mice. The Administrative Core will provide general support and organize the biannual Seattle Muscular Dystrophy Conference. The Mouse Biology Core will provide assistance with functional and pathological analyses of mouse models to each project. The results derived from this integrated program project will lead to new therapeutic approaches for DMD and other diseases of muscle degeneration.