Reducing dynamin 2 (DNM2) rescues <i>DNM2</i>-related dominant centronuclear myopathy.

Abstract

Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. We have previously shown that reduction of the large GTPase DNM2 in a mouse model of the X-linked form, due to loss of myotubularin phosphatase MTM1, prevents the development of the skeletal muscle pathophysiology. As <i>DNM2</i> is mutated in autosomal dominant forms, here we tested whether DNM2 reduction can rescue <i>DNM2</i>-related CNM in a knock-in mouse harboring the p.R465W mutation (<i>Dnm2</i>^RW/+) and displaying a mild CNM phenotype similar to patients with the same mutation. A single intramuscular injection of adeno-associated virus-shRNA targeting <i>Dnm2</i> resulted in reduction in protein levels 5 wk post injection, with a corresponding improvement in muscle mass and fiber size distribution, as well as an improvement in histopathological CNM features. To establish a systemic treatment, weekly i.p. injections of antisense oligonucleotides targeting <i>Dnm2</i> were administered to <i>Dnm2</i>^RW/+mice for 5 wk. While muscle mass, histopathology, and muscle ultrastructure were perturbed in <i>Dnm2</i>^RW/+mice compared with wild-type mice, these features were indistinguishable from wild-type mice after reducing DNM2. Therefore, DNM2 knockdown via two different strategies can efficiently correct the myopathy due to <i>DNM2</i> mutations, and it provides a common therapeutic strategy for several forms of centronuclear myopathy. Furthermore, we provide an example of treating a dominant disease by targeting both alleles, suggesting that this strategy may be applied to other dominant diseases.