Allele‐specific silencing therapy for Dynamin 2‐related dominant centronuclear myopathy

Rapid advances in allele‐specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal‐dominant centronuclear myopathy ( CNM ), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM 2 gene encoding Dynamin 2. Allele‐specific si RNA sequences were developed in order to specifically knock down the human and murine DNM 2 ‐ mRNA harbouring the p.R465W mutation without affecting the wild‐type allele. Functional restoration was achieved in muscle from a knock‐in mouse model and in patient‐derived fibroblasts, both expressing the most frequently encountered mutation in patients. Restoring either muscle force in a CNM mouse model or DNM 2 function in patient‐derived cells is an essential breakthrough towards future gene‐based therapy for dominant centronuclear myopathy.