Recombinant adeno-associated viral (AAV) vectors are powerful vehicles for in vivo delivery of therapeutic transgenes. Tissue tropism and consequently vector dosage for gene therapy can vary amongst naturally occurring and engineered AAV serotypes. We previously reported that serotype 8 AAV-mediated MTM1 gene delivery can correct the phenotype of murine and canine models of myotubular myopathy, a severe pediatric disorder leading to generalized muscle weakness and respiratory failure in patients.

In order to identify AAV vectors with increased skeletal muscle potency in myotubularin deficient muscle, in the present study we compared the biodistribution and transgene expression of serotype 8, 9 and rh10 vectors with AAVpo1 of porcine origin, and its derivative AAVpo1A1, carrying a MTM1 expression cassette. Each vector was administrated intravenously in wild-type and Mtm1 KO mice and tissues were harvested 4 weeks post-injection. We found that administration of AAV9-, AAVrh10- and AAVpo1A1 vectors resulted in higher myotubularin expression levels in skeletal muscles compared to AAV8- and AAVpo1 vectors. In addition, the AAVpo1A1 vector detargeted liver transduction. Therefore, a dose-response study was performed in mutant mice to assess the potency of the AAVpo1A1-MTM1 vector in treating myotubular myopathy over a 3-month period. At a single dose of 2x10¹³vg/kg, this vector prolonged survival and corrected muscle pathology and strength in Mtm1 KO mice. These results indicate that AAVpo1A1 vectors might be useful for gene therapy of myotubular myopathy.