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

Rhodopsin (Rho) 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 the Rho mutant, while replacing normal rhodopsin in a rhodopsin mutation mouse model. When Rho-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 for Rho mutant ADRP, as well as new directions for future clinical research on the treatment of such gain-of-function genetic diseases.