Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. Here, the authors used this strategy for autosomal-dominant centronuclear myopathy (AD-CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM2 gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine DNM2-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. This study establishes the proof of concept of allele‐specific silencing to correct the most frequent DNM2 mutation responsible for AD‐CNM. This is also the first evidence of functional rescue obtained both in CNM human cells and in mouse model.
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Trochet D, Prudhon B, Beuvin M, et al. Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy. EMBO Mol Med. 2017 Dec 15.
