The sarcoglycan complex stabilizes the plasma membrane of muscle, and mutations in the genes encoding sarcoglycan subunits produce a fragile sarcolemma. Sarcolemmal disruption is a general feature of skeletal and cardiac muscle injury, as well as the myopathic disorders arising from dystrophin or sarcoglycan gene mutations. This research program has as its primary goal to understand the mechanisms by which dystrophin and sarcoglycan stabilize the sarcolemma and to identify genetic modifiers of muscular dystrophy. Because these rare genetic disorders share features with muscle injury, including cardiac muscle injury, we hypothesize that modifiers of sarcoglycan mutations will not only exert as similar effect on dystrophinopathies but also on muscle injury in general. We mapped genetic modifiers using a mouse model of sarcoglycanopathy, the Sgcg model which lacks gamma-sarcoglycan. This model was selected because there was strong evidence for modifiers in humans with sarcoglycan gene mutations. We used an intercross strategy in Sgcg mice, taking advantage of the mild protective phenotype seen in the 129 genetic background and the severe phenotype seen in Sgcg mice on the deleterious DBA background. We successfully identified multiple genetic modifiers including latent TGF? binding protein 4 (LTBP4) and annexin A6 (ANXA6). Both modifier genes are biologically linked to injury repair and recovery and validate the utility of the method. Concomitant with this progress, there have advances in the development and approval of antisense oligonucleotide-mediated exon skipping as a therapy for Duchenne Muscular Dystrophy. We developed a similar approach to treat Limb Girdle Muscular Dystrophy (LGMD) 2C, which is the form of muscular dystrophy from ?-sarcoglycan gene mutations. In the last period of support, we showed the feasibility of exon skipping in cell lines generated from multiple patients with LGMD 2C mutations, demonstrating that Mini-gamma, the small internally deleted form of gamma-sarcoglycan stabilizes the sarcolemma. We will now focus on combining exon skipping together with modifier approaches to elicit genetic correction and promote sarcolemmal stability. We will develop preclinical data to support exon skipping and simultaneously demonstrate key biological mechanisms about the relationship between sarcolemmal stability and muscle growth.
This work is designed to test a genetic correction method called exon skipping for Limb Girdle Muscular Dystrophy. The methods used in this work will help advance these therapies and provide new information about pathways that can improve heart and muscle function in these and related diseases.
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