Retinal degeneration in a mouse model of CRB1 disease rescued by the photoreceptor-specific CRB1-B isoform
TL;DR
It is found that restoring CRB1-B to photoreceptors prevents degeneration and completely rescues visual function, despite the absence of other isoforms, and suggests that exploring disease gene isoform diversity offers an untapped opportunity to devise novel therapeutics.
Abstract
Many genes involved in inherited diseases produce alternate mRNA isoforms that remain poorly characterized. Functional assessment of these isoforms could therefore unlock new insights into disease pathobiology or treatment. Here we investigated the function of the newly discovered “B” isoform of CRB1, a gene implicated in inherited retinal degenerations. CRB1-B is the most abundant retinal isoform, and differs from the canonical CRB1-A isoform in several important ways. Crucially, CRB1-B is the only isoform expressed by photoreceptors – the cells vulnerable to degeneration. Using a mouse model of CRB1-associated degeneration with degraded visual acuity, we find that restoring CRB1-B to photoreceptors prevents degeneration and completely rescues visual function, despite the absence of other isoforms. The therapeutic mechanism involves preservation of adherens junctions between photoreceptors and supporting glia: We establish that progressive loss of these junctions is a key pathobiological mechanism underlying photoreceptor death, and that junction loss is prevented by restoring photoreceptor expression of CRB1-B. Our findings nominate CRB1-B replacement as a promising gene therapy strategy. More broadly, they suggest that exploring disease gene isoform diversity offers an untapped opportunity to devise novel therapeutics.