A genome-wide in vivo CRISPR screen identifies neuroprotective strategies in the mouse and human retina.

Retinitis pigmentosa (RP) is a genetically diverse blinding disorder lacking broadly effective therapies. We performed a genome-wide in vivo CRISPR knockout screen in mice carrying the rhodopsin mutation (the most common cause of autosomal dominant RP in the United States) to systematically identify neuroprotective genes. We discovered multiple knockouts that accelerated rod photoreceptor loss, validated top candidates, and showed that overexpressing two genes- and -preserved rods and cones, maintained retinal function, and improved visual behaviors. To accelerate translation, we developed a human RP model in adult retinal explants, recreating key disease features. and augmentation prevented photoreceptor loss in human retinas. Our findings establish a pipeline for systematic identification and translational testing of neuroprotective genes in mouse and human RP models, provide a novel set of validated candidate genes, and underscore the therapeutic promise of and as mutation-agnostic strategies to preserve vision.