Knockout and replacement gene surgery to treat rhodopsin-mediated autosomal dominant retinitis pigmentosa.

Mutations in the Rhodopsin (RHO) gene are the predominant causes of autosomal dominant retinitis pigmentosa (adRP). Given the diverse gain-of-function mutations, therapeutic strategies targeting specific sequences face significant challenges. Here, we provide a universal approach to conquer this problem: we have devised a CRISPR-Cas12i-based, mutation-independent gene knockout and replacement compound therapy carried by a dual AAV8 system. In this study, we successfully delayed the progression of retinal degeneration in the classic mouse disease model Rho P23H , and also Rho P347S , a new native mouse mutation model we developed. Our research expands the horizon of potential options for future treatments of rhodopsin-mediated autosomal dominant retinitis pigmentosa (RHO-mediated adRP).