O.6 Restricting MTM1 transgene expression to skeletal muscle in AAV-mediated gene therapy for myotubular myopathy

Myotubular myopathy (XLMTM) is a severe congenital disease that affects skeletal musculature, which is characterized by the presence of small myofibers with frequent occurrence of central nuclei. The disease is due to mutations in the MTM1 gene, encoding a phosphoinositide phosphatase named myotubularin, and specific treatment is currently unavailable. We have previously demonstrated the efficacy of local administration of AAV vectors carrying the Mtm1 cDNA to treat the disease, and have more recently extended these studies to the whole body. In order to express MTM1 preferentially in skeletal muscles after systemic gene delivery, we have constructed several AAV vectors that contain the Mtm1 cDNA under the potent desmin promoter and miRNA target sequences for cardiac detargeting. We show that intravenous delivery of these vectors 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 demonstrate that this strategy is very efficient to drive selected expression of transgenes in skeletal muscles, avoiding potential side effects in heart, and is useful for the treatment of disorders that mainly affect the skeletal musculature, such as myotubular myopathy.