Gene Therapy for Cardiac and Skeletal Myopathies

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DESCRIPTION (provided by applicant): Pompe disease (1:40000 live births, glycogen storage disease type II, acid maltase deficiency; MIM 232300) is characterized by severe cardiomyopathy and respiratory muscle weakness that affects individuals at an early age. These effects are mediated by a single defective gene encoding the enzyme acid a-glucosidase (GAA), resulting in glycogen accumulation within muscle tissue. Glycogen deposits disrupt the architecture and function of both cardiac and skeletal muscle and cause a debilitating and often fatal condition. Presently, there is no effective cure for Pompe disease and treatment options are severely limited. Enzyme replacement therapy (ERT), the only approved treatment for Pompe disease, must be administered frequently and only provides partial benefit to the patient. Therefore, the focus of our laboratory is to develop a novel therapeutic approach to reverse or ameliorate the effects of Pompe disease. Included in this proposal are two studies aimed to establish the efficacy and degree of correction utilizing recombinant adeno-associated viral (rAAV)-mediated delivery of GAA in an animal model of Pompe disease. Specific Aims: 1) To test the hypothesis that systemic delivery of rAAV encoding hGAA attenuates cardioskeletal myopathy; 2) To test the hypothesis that administration of rAAV2/9-hGAA therapy in an aged animal model will result in correction of advanced stages of Pompe disease. Taken together, the proposed work will provide new insights into the manner in which gene therapy can correct GAA deficient tissue. Aside from its relevance to patients with Pompe disease, this work will have a profound impact by offering a novel therapeutic option to patients who present alternative cardiovascular and skeletal muscle disease.