Journal
EMBO MOLECULAR MEDICINE
Volume 10, Issue 2, Pages 239-253Publisher
WILEY
DOI: 10.15252/emmm.201707988
Keywords
allele-specific silencing therapy; centronuclear myopathy; Dynamin 2; RNA interference
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Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Association Institut de Myologie (AIM)
- Universite Pierre et Marie Curie (UPMC)
- Centre National de la Recherche Scientifique (CNRS)
- Agence Nationale de la Recherche [ANR-14-CE12-0009, ANR-14-CE12-0001-01]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE12-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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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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