Optimized allele-specific silencing of the dominant-negative <i>COL6A1</i> G293R substitution causing collagen VI-related dystrophy.

ABSTRACT: Collagen VI-related dystrophies (COL6-RDs) are a group of severe, congenital-onset muscular dystrophies for which there is no effective causative treatment. Dominant-negative mutations are common in COL6A1, COL6A2, and COL6A3 genes, encoding the collagen α1, α2, and α3 (VI) chains. They act by incorporating into the hierarchical assembly of the three α (VI) chains and consequently produce a dysfunctional collagen VI extracellular matrix, while haploinsufficiency for any of the COL6 genes is not associated with disease. Hence, allele-specific transcript inactivation is a valid therapeutic strategy, although selectively targeting a pathogenic single nucleotide variant is challenging. Here, we develop a small interfering RNA (siRNA) that robustly, and in an allele-

SUBMITTER: Brull A 

PROVIDER: S-EPMC11015156 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature