Allele-specific gene silencing by RNA interference is a promising therapeutic approach for dominant hereditary diseases. This strategy is based on the targeted inhibition of messenger RNA (mRNA) from the mutated allele, while preserving the expression of the healthy allele.
A team at the Institute’s Centre for Research in Myology* has developed this strategy for Schuurs-Hoeijmakers syndrome (SHMS), a rare neurodevelopmental disorder for which no treatment is currently available. The majority of SHMS cases are caused by a recurrent heterozygous missense mutation in the PACS1 gene.
Using fibroblasts from patients, the team identified several small interfering RNA (siRNA) sequences capable of specifically inhibiting the expression of mutated PACS1 mRNA while sparing wild-type mRNA. Transcriptomic analysis of these fibroblasts revealed alterations in the organisation of the extracellular matrix in mutant cells, including overexpression of COL8A1 and increased extracellular deposition. Treatment of cells with the most effective allele-specific siRNA corrected the deregulation of COL8A1.
This study provides solid proof of concept for allele-specific RNA interference treatment of SHSM in patient-derived cells and highlights a new pathophysiological mechanism involving extracellular matrix dysfunction in this disease.
Taken together, these results reinforce allele-specific gene silencing as a robust, safe and effective therapeutic strategy for the treatment of dominant inherited diseases.
* L. Mekzine et K. Mamchaoui : Cellular and molecular orchestration in muscle regeneration, during ageing and in pathologies, CRM
N. Pinzon et M. Kondili : MyoData platform
B. Cadot : Signaling pathways & striated muscles, CRM
D. Trochet et M. Bitoun : Muscle organization & therapy of dominant centronuclear myopathy, CRM
