Bioengineered AAV vectors with increased skeletal muscle potency and specificity for systemic gene therapy of myotubular myopathy
Résumé
X-linked myotubular myopathy (XLMTM) is a severe congenital disorder characterized by generalized hypotonia and muscle weakness, frequently associated with fatal respiratory failure. The disease is caused by loss-of-function mutations in the MTM1 gene, which encodes myotubularin. We demonstrated the therapeutic efficacy of intravenous delivery of serotype 8 adeno-associated viral vectors (AAV8) expressing myotubularin in murine and canine animal models of the disease, representing the basis of an ongoing clinical trial in patients.
In the present study, we generated and assessed the efficacy of two novel AAV vectors, AAVS1P1 and AAVS10P1, which are composed of hybrid capsids and a small VP1 peptide insertion, in Mtm1-KO mice. Intravenous administration of either AAVS1P1- or AAVS10P1-MTM1 vectors prolonged the lifespan of mutant animals and resulted in a higher increase in muscle mass, strength, and transgene expression compared to AAV8-MTM1 at the same dose, and in liver transduction detargeting. Our findings indicate that these novel vectors are more potent than AAV8 in rescuing the phenotype of myotubular myopathy mice, and hold great potential for gene therapy of other inherited disorders affecting skeletal muscles.