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Journal Articles EMBO Molecular Medicine Year : 2018

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

Abstract

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 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. Restoring either muscle force in a CNM mouse model or DNM2 function in patient-derived cells is an essential breakthrough towards future gene-based therapy for dominant centronuclear myopathy.
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Dates and versions

hal-02000303 , version 1 (31-01-2019)

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Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, et al.. Allele‐specific silencing therapy for Dynamin 2‐related dominant centronuclear myopathy. EMBO Molecular Medicine, 2018, 10 (2), pp.239-253. ⟨10.15252/emmm.201707988⟩. ⟨hal-02000303⟩
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