AAV-delivered RNAi-based gene therapy targeting rhodopsin

AAV-delivered RNAi-based gene therapy targeting rhodopsin refers to a therapeutic approach, most notably exemplified by the candidate IC-100, designed to treat autosomal dominant retinitis pigmentosa (adRP) caused by mutations in the rhodopsin (RHO) gene. This strategy utilizes an adeno-associated virus (AAV) vector—typically AAV2/5—to deliver a mutation-independent 'knockdown-and-replacement' system to photoreceptor cells. The therapy incorporates an RNA interference (RNAi) component, such as a short hairpin RNA (shRNA) or microRNA, which silences both mutant and wild-type endogenous RHO mRNA. Simultaneously, it delivers a codon-modified RHO replacement cDNA that is resistant to the RNAi-mediated silencing, thereby restoring functional rhodopsin protein levels. This approach aims to eliminate the toxic effects of mutant rhodopsin while maintaining physiological protein expression regardless of the specific underlying mutation. IC-100 was originally developed by Iveric Bio (now an Astellas company) in collaboration with the University of Florida and the University of Pennsylvania, while similar microRNA-based strategies are being explored by academic institutions such as the University of Oxford.