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Abstract

The dystrophin complex is a multi-protein complex that has both structural and signaling roles in cardiac and skeletal muscle. Loss-of-function mutations in the genes encoding dystrophin, or the associated sarcoglycan proteins, lead to myofiber loss and muscle degeneration. The structure-function correlation between predicted protein structure and clinical outcomes has been extensively cataloged for dystrophin mutations. Studies in animal models also shed light on the dystrophin regions necessary for in vivo function. Together, these findings provided the justification for testing exon skipping strategies to restore dystrophin protein in human patients. Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. With exon skipping, antisense oligonucleotides target RNA to bypass premature stop codons and restore reading frame disruption. Exon skipping is currently being evaluated in humans with Duchenne Muscular Dystrophy and dystrophin gene mutations. For Duchene Muscular Dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We now expanded the potential for exon skipping by testing the functionality of an internal, in-frame deletion of a transmembrane protein, γ-sarcoglycan. We generated Mini-gamma by deleting a large portion of the extracellular domain, and showed that Mini-Gamma provided functional and pathological benefit to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. Since Mini-Gamma represents removal of four of the seven coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.

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