Gene replacement rescues severe muscle pathology and prolongs survival in myotubularin-deficient mice and dogs

We previously reported in Science Translational Medicine (STM) unprecedented results (1) from gene replacement experiments in MTM1-mutant animal models of X-linked myotubular myopathy (XLMTM, OMIM 310400) (2). This devastating congenital muscle disorder results from deficiency of myotubularin, a phosphatidylinositol-3-phosphatase required for skeletal muscle function, growth and ultrastructural organization (3-6). The overall median survival of XLMTM patients is only 29 months (7) and the majority of patients who survive beyond two years require ventilator support (8). While intensive medical support extends the life of young patients, there is no effective treatment. Of therapeutic approaches tested in animal models of XLMTM, gene replacement targets the underlying cause of this monogenic disorder (9). Analogous to human XLMTM patients, mice engineered with a targeted deletion in the Mtm1 gene demonstrate marked muscle weakness and shortened lifespan (4). A naturally occurring MTM1 missense mutation in dogs results in a similar phenotype with reduction of muscle strength and lifespan (10). As we reported in STM, myotubularin-deficient mice and dogs both responded to systemic and quasi-systemic administration of a recombinant serotype 8 adeno-associated virus (AAV8) carrying full-length murine Mtm1 or canine MTM1 coding sequence. Both mouse and dog models responded within a few short weeks with rapid and sustained increases to near normal levels of muscle strength and prolonged survival.