Publications by authors named "Gerry Clark"
Extensive mutational heterogeneity presents a significant barrier to the development of therapeutics for RDS-peripherin-linked autosomal-dominant retinitis pigmentosa (RP), for which more than 50 disease-related mutations have been identified to date. Mutation-independent suppression, using RNA interference (RNAi), together with simultaneous expression of a replacement rds gene (r-rds, which has been altered to escape suppression but nevertheless encodes wild-type protein) has been explored in COS-7 cells and mouse retinal explants. The efficacy of small interfering and short hairpin RNAs (si/shRNAs) silencing mouse rds, and the function of r-rds (containing degenerate substitutions in the RNAi target sequence) were analyzed at transcript (RT-PCR) and protein (ELISA) levels in COS-7 cells.
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- The challenge of intragenic heterogeneity in dominant disease-causing genes complicates the development of effective and affordable treatments, as seen in autosomal dominant retinitis pigmentosa caused by numerous rhodopsin mutations.
- An RNA interference (RNAi)-based method is proposed that can target the problematic native transcripts without affecting engineered replacement genes, suggesting a mutation-independent therapeutic strategy.
- Experiments show that this RNAi approach can reduce murine rhodopsin levels by up to 90% while still allowing the expression of the replacement genes, validating its effectiveness in cell cultures and live mouse models.