CRISPR/SaCas9-based gene editing rescues photoreceptor degeneration throughout a rhodopsin-associated autosomal dominant retinitis pigmentosa mouse model.

Abstract

Rhodopsin () gene mutation was considered the highest prevalent mutation in autosomal dominant retinitis pigmentosa (ADRP); however, effective therapeutics for ADRP have not been developed. The process of gene editing via the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system offers the potentiality to provide cures for dominantly inherited disorders. Herein, we generated a CRISPR/SaCas9-mediated gene reduction system to inactivate themutant, while replacing normal rhodopsin in a rhodopsin mutation mouse model. When-P23H knock-in mice were administered a subretinal injection of the "reduction and replacement" system, the expression of mutant rhodopsin was reduced, and retinal function was improved. Therefore, we concluded that CRISPR/SaCas9-based "reduction and replacement" gene therapy could provide structural and functional benefits formutant ADRP, as well as new directions for future clinical research on the treatment of such gain-of-function genetic diseases.