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

Here, we conduct a genome-wide in vivo CRISPR screen in rod photoreceptors to evaluate the neuroprotective potential of every gene in the genome. We performed this screen in mice carrying the rhodopsin P23H mutation, the most common cause of autosomal dominant retinitis pigmentosa in the United States (accounting for 15-18% of cases), which leads to photoreceptor degeneration through rhodopsin misfolding and ER stress. Our genome-wide screen identified a set of neuroprotective candidate genes with potential for therapeutic applications in the eye and beyond. A secondary screen confirmed the top hits, and we developed gene therapy vectors for two candidates. These vectors effectively preserved retinal structure, function, and visual behaviors in P23H mice.