Project 1 will focus on expanding the clinical usefulness of GALGT2 gene therapy using rAAVrh74.MCK.GALGT2. rAAVrh74.MCK.GALGT2 is a surrogate gene therapy that stimulates the overexpression of the human GALGT2 gene in skeletal and cardiac muscle. This vector stimulates changed glycosylation of the muscle membrane, including glycosylation of ? dystroglycan, such that it mimics glycosylation normally found at the neuromuscular and myotendinous junctions, and increases the extrasynaptic expression of dystrophin and laminin ?2 surrogates that are known to inhibit muscular dystrophy. Preclinical studies have shown that muscle GALGT2 overexpression inhibits disease in mouse models of Duchenne Musuclar Dystrophy (DMD), Congenital Muscular Dystrophy 1A (CMD1A) and Limb Girdle Muscular Dystrophy 2D (LGMD2D). This vector utilizes an AAV serotype, rh74, that shows great efficacy at delivering gene expression to muscles when the vector is delivered via the blood, while the MCK promoter confines gene expression to muscle cells. Extensive proof-of-concept and safety studies have led to an IND for the use of rAAVrh74.MCK.GALGT2 in patients with DMD. While those clinical trials are beginning, we wish here to perform proof of concept studies that would allow for the expanded use of rAAVrh74.MCK.GALGT2 to patients with CMD1A and LGMD2D. Further studies are aimed at expanded the usefulness of rAAVrh74.MCK.GALGT2 gene therapy in DMD patients by studying whether this gene therapy can increase the therapeutic effectiveness of exon skipping therapy or therapy involving gene overexpression of follistatin, a myostatin inhibitor that builds new muscle mass. All of the experiments proposed here are directed toward rapid translation of novel therapeutic approaches for muscular dystrophies, which is the overarching goal of this CORT proposal.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1)
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Nationwide Children's Hospital
United States
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Xu, Rui; Jia, Ying; Zygmunt, Deborah A et al. (2018) An Isolated Limb Infusion Method Allows for Broad Distribution of rAAVrh74.MCK.GALGT2 to Leg Skeletal Muscles in the Rhesus Macaque. Mol Ther Methods Clin Dev 10:89-104
Wallace, Lindsay M; Saad, Nizar Y; Pyne, Nettie K et al. (2018) Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. Mol Ther Methods Clin Dev 8:121-130
Giesige, Carlee R; Wallace, Lindsay M; Heller, Kristin N et al. (2018) AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight 3:
Zygmunt, Deborah A; Crowe, Kelly E; Flanigan, Kevin M et al. (2017) Comparison of Serum rAAV Serotype-Specific Antibodies in Patients with Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Inclusion Body Myositis, or GNE Myopathy. Hum Gene Ther 28:737-746