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

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 treatm...

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Bibliographic Details
Main Authors: Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, Laura Julien, Sofia Benkhelifa‐Ziyyat, Aymen Rabai, Kamel Mamchaoui, Arnaud Ferry, Jocelyn Laporte, Pascale Guicheney, Stéphane Vassilopoulos, Marc Bitoun
Format: Article
Language:English
Published: Wiley 2018-02-01
Series:EMBO Molecular Medicine
Subjects:
allele‐specific silencing therapy
centronuclear myopathy
Dynamin 2
RNA interference
Online Access:https://doi.org/10.15252/emmm.201707988
Description
Summary: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.
ISSN:1757-4676
1757-4684

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