Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy.
Delphine TrochetBernard PrudhonMaud BeuvinCécile PeccateStéphanie LorainLaura JulienSofia Benkhelifa-ZiyyatAymen RabaiKamel MamchaouiArnaud FerryJocelyn LaportePascale GuicheneyStéphane VassilopoulosMarc BitounPublished in: EMBO molecular medicine (2019)
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.
Keyphrases
- wild type
- mouse model
- late onset
- end stage renal disease
- skeletal muscle
- endothelial cells
- newly diagnosed
- induced apoptosis
- ejection fraction
- copy number
- early onset
- genome wide
- muscular dystrophy
- peritoneal dialysis
- prognostic factors
- single molecule
- gene expression
- signaling pathway
- cancer therapy
- decision making
- genome wide identification
- combination therapy