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

Delphine Trochet (1) , Bernard Prudhon (1, 2) , Maud Beuvin (1, 2) , Cécile Peccate (1, 2) , Stéphanie Lorain (1, 2) , Laura Julien (1, 2) , Sofia Benkhelifa‐ziyyat (1, 2) , Aymen Rabai (3, 4, 5) , Kamel Mamchaoui (1) , Arnaud Ferry (1, 2) , Jocelyn Laporte (3, 5, 4, 1) , Pascale Guicheney (6) , Stéphane Vassilopoulos (1) , Marc Bitoun (1, 2)

1 Centre de recherche en Myologie – U974 SU-INSERM
2 Institut de Myologie
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
4 CdF (institution) - Collège de France
5 UNISTRA - Université de Strasbourg
6 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

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.

Mots clés: allele-specific silencing therapy; RNA interference; centronuclear myopathy; Dynamin 2

Domaines: Génétique humaine; Médecine humaine et pathologie

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⟩