Optimized allele-specific silencing of the dominant-negative COL6A1 G293R substitution causing collagen VI-related dystrophy
Astrid Brull, Apurva Sarathy, Véronique Bolduc, Grace S. Chen, Riley M. McCarty, Carsten G. Bönnemann
Abstract
gene. By intentionally introducing an additional mismatch into the siRNA design, we achieved enhanced specificity toward the mutant allele. Treatment of patient-derived fibroblasts effectively reduced the levels of mutant transcripts while maintaining unaltered wild-type transcript levels, rescuing the secretion and assembly of collagen VI matrix by reducing the dominant-negative effect of mutant chains. Our findings establish a promising treatment approach for patients with the recurrent dominantly negative acting G293R glycine substitution.
Topics & Concepts
Collagen VIMuscular dystrophyGeneticsAlleleCongenital muscular dystrophySubstitution (logic)MedicineBiologyExtracellular matrixGeneComputer scienceProgramming languageCell Adhesion Molecules ResearchRNA Interference and Gene DeliveryMuscle Physiology and Disorders