Abstract
Myotubular myopathy (XLMTM) is a fatal pediatric disease of skeletal muscle due to mutations in the MTM1 gene. Patients with XLMTM typically present with generalized muscle weakness and respiratory failure. We have previously demonstrated the efficacy of AAV-mediated MTM1 gene therapy in animal models. In order to express MTM1 preferentially in skeletal muscles after systemic gene delivery, we have constructed AAV vectors that contain the Mtm1 cDNA under the potent desmin promoter and a miRNA-208a target sequence for cardiac detargeting. We show that intravenous delivery of this vector leads to myotubularin expression in skeletal muscles scattered throughout the body, including the diaphragm, and reduced expression in heart. We have selected one of these vectors for gene therapy in XLMTM mice and show the results in survival, pathology and contractile force. We also analyzed the long-term effect of the transgene in miRNA-208a level and gene expression in heart.
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