Novel therapeutics strategies for Duchenne MD

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The overall objective of this proposal is to explore the therapeutic potential of improving muscle cell membrane maintenance and repair for the treatment of Duchenne muscular dystrophy. In particular, the proposal will test these hypotheses: 1) Overexpression of the glycosyltransferase, LARGE, will stabilize the sarcolemma in mdx muscle and thus prevent or delay muscle pathology; and 2) Overexpression of dysferlin will improve muscle membrane repair in mdx mice and thus prevent or delay muscle pathology. In Duchenne muscular dystrophy patients and mdx mice, the absence of dystrophin leads to a reduction of dystroglycan at the sarcolemma and disruption in the link between the sarcolemma and the extracellular matrix. We have previously demonstrated that Overexpression of LARGE will increase the glycosylation and laminin binding activity of alpha-dystroglycan in wild type muscle. We hypothesize that LARGE-dependant hyperglycosylation of alpha-dystroglycan in mdx muscle will maintain alpha-dystroglycan at the sarcolemma and thereby stabilize the muscle membrane and its link with extracelluar matrix in the absence of dystrophin. The first aim will test this hypothesis using viral-mediated Overexpression of LARGE in mdx muscle and LARGE transgenic mice crossed with mdx mice. In the second aim we propose that an increased and sustained expression of dysferlin in mdx muscle will prevent pathology by improving membrane repair. Recently, studies on dysferlin-null mice have revealed a new mechanism of muscle pathogenesis where membrane repair, and not structural integrity, of the sarcolemma is abnormal. Our preliminary data on dystrophin/dysferlin-null mice suggests that dysferlin may play a role in diminishing mdx muscle pathology because the dystrophic changes are more severe in the absence of both proteins. To test this hypothesis, mdx mice will be treated with dysferlin-expressing adenovirus or crossed with dysferlin transgenic mice. Therefore, this project will investigate the potentially beneficial functional and physiological consequences of increased expression of LARGE or dysferlin. Focusing on endogenous proteins like LARGE or dysferlin, whose activity could potentially be modulated, will provide a platform for new targets of therapy (possibly pharmacological treatments) aimed at upregulating LARGE or dysferlin expression and/or activity to treat Duchenne muscular dystrophy.