629. Intravenous Delivery of a MTMR2-Encoding AAV9 Vector Extends Lifespan and Improves Muscle Function in Mice with X-Linked Myotubular Myopathy

Abstract

X-linked myotubular myopathy is a rare genetic disease affecting the skeletal musculature. Male patients present profound neonatal muscle hypotonia and weakness, respiratory insufficiency, and in most cases have a very severe reduction in lifespan. At the pathological level, muscle fibers are hypotrophic and contain central nuclei with disorganized mitochondria and triads. The disease is caused by mutations in the MTM1 gene, which encodes myotubularin, the founder member of a family of 15 homologous proteins in mammals (including MTMR1 to 14). We recently demonstrated the therapeutic efficacy of intravenous delivery of rAAV vectors expressing MTM1 in murine and canine models of myotubular myopathy. In the present study, we tested whether Mtmr1 and Mtmr2 overexpression, Mtm1 closest homologs, could also rescue the XLMTM phenotype. Recombinant serotype-9 AAV vectors encoding either MTM1, MTMR1 or MTMR2 under the control of the desmin promoter were compared by injection into the tibialis anterior muscle of two-week-old Mtm1 deficient mice. Two weeks after vector delivery, a therapeutic effect was observed with Mtm1 and Mtmr2, but not Mtmr1, with Mtm1 being the most efficacious transgene. We further explored a systemic route of administration, intravenous injection of a single dose of rAAV9-Mtmr2 in XLMTM mice ameliorated muscle histology and strength, and extended lifespan throughout the 3-month period of the study. Even though Mtmr2-treated mutant mice remained smaller than their wild-type counterparts, with partial increase in body weight and myofiber size, most importantly, the contractile force of myotubularin-deficient muscles improved strongly. Altogether, these results establish the proof-of-concept that overexpression of MTMR2 in skeletal muscle represents a novel therapeutic approach for myotubular myopathy.