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 t...

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Bibliographic Details
Published in:EMBO molecular medicine 2017-12, Vol.10, p.239-253
Main Authors: Trochet, Delphine, Prudhon, Bernard, Beuvin, Maud, Peccate, Cécile, Lorain, Stéphanie, Julien, Laura, Benkhelifa‐ziyyat, Sofia, Rabai, Aymen, Mamchaoui, Kamel, Ferry, Arnaud, Laporte, Jocelyn, Guicheney, Pascale, Vassilopoulos, Stéphane, Bitoun, Marc
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Language:English
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Life Sciences
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Summary: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.
ISSN:1757-4676
1757-4684
DOI:10.15252/emmm.201707988