Gene delivery of MG53 for muscle membrane repair and functional improvement in a

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DESCRIPTION (provided by applicant): Defects in muscle cell membrane integrity have been linked to various types of muscular dystrophies (MDs). Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies (DMD and BMD), while mutations in sarcoglycan (SG) genes because limb girdle muscular dystrophies (LGMDs). Today, more than 30 different genes have been identified to cause different types of MD, and they are all rare (orphan) diseases. However, the majority of MDs share similar pathological consequences from sarcolemma damage, such as elevated serum creative kinase (CK) activity, profound myofiber degeneration, and muscle wasting and weakness. Therefore, a therapeutic strategy that aims at repairing the leaky cell membranes instead of targeting each specific genetic mutation should be beneficial to many types of MD. Gene therapy targeted at muscle membrane repair and remodeling shows promise. The long- term goal is to use MG53 to restore sarcolemma integrity to any dystrophic muscle, irrespective of the hereditary or acquired origin. The immediate goal of this proposal is to determine whether systemic gene delivery of MG53 (an essential component of the membrane repair machinery) by AAV8 can render efficient in vivo initiation of sarcolemma repair, systemic rescue of skeletal muscle function, and substantial improvement of overall health in a delta-sarcoglycan-deficient Syrian hamster model, a well-established muscular dystrophy and congestive heart failure animal model. There are two specific aims: 1) to study long-term muscle membrane repair mediated by hMG53 in the TO-2 hamster model after AAV8 systemic delivery; 2) to investigate the histopathology, physiology, and whole-body functional improvement in TO-2 hamsters after AAV8-hMG53 systemic delivery. PUBLIC HEALTH RELEVANCE: The novelty of this proposal comes from the unique therapeutic concept of preventing the manifestation of muscular dystrophy by overexpressing hMG53 to restore muscle membrane integrity instead of targeting each genetic mutation responsible for causing the different types of muscular dystrophy. MG53-mediated muscle membrane repair and remodeling could clinically become an alternative therapy for any membrane leakage or disruption of muscle, including any type of muscular dystrophy and other non-genetic diseases or injuries.