Reducing dynamin 2 corrects DNM2-related dominant centronuclear myopathy

Centronuclear myopathies (CNM) are a group of severe muscle diseases for which no effective therapy is currently available. The authors of the present study 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. Given that DNM2 is mutated in autosomal dominant forms, here they tested whether DNM2 reduction can rescue DNM2-related CNM in a knock-in mouse harboring the p.R465W mutation (Dnm2 RW/+) and displaying a mild CNM phenotype similar to patients with the same mutation. A single intramuscular injection of adeno-associated virus-shRNA targeting Dnm2 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 Dnm2 were administered to Dnm2 RW/+mice for 5 wk. While muscle mass, histopathology, and muscle ultrastructure were perturbed in Dnm2 RW/+mice compared with wild-type mice, these features were indistinguishable from wild-type mice after reducing DNM2.

 

Buono S, Ross JA, Tasfaout H, et al. Reducing dynamin 2 (DNM2) rescues DNM2-related dominant centronuclear myopathy. Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11066-11071