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Retinitis pigmentosa (RP) is a class of diseases that lead to progressive degeneration of the retina, the most common form of inherited retinal dystrophy, affecting about 1 in 4000 people worldwide. The individuals affected by RP first experience peripheral and night vision loss, followed by central vision loss, eventually legal blindness. The inheritance pattern of RP has been identified as autosomal dominant (30-40%), autosomal recessive (50-60%), X-linked (5-10%). Mutations in more than sixty genes have been identified so far associated with autosomal dominant RP, among which those in the RP1 gene account for 5-7%. A large fraction of RP caused by the mutant RP1 gene (designated retinitis pigmentosa 1) is inherited as autosomal dominant with most of the mutations clustered at exon 4 of RP1 gene, among which the RP1-Q667X mutation is the most frequent one.
We previously generated a RP1-Q662X knockin mouse model which genetically and phenotypically mimics the retinitis pigmentosa 1 caused by the RP1-Q667X mutation in human patient. By studying this mouse model, we have discovered that the dominant mutations in the RP1 gene cause retinitis pigmentosa 1 through a dominant negative mechanism. Based on these results, we aim to develop a gene augment therapy using viral vectors to deliver a wild type copy of the RP1 gene into the retina in the RP1-Q662X mice, which may prevent the photoreceptor denegation upon delivery, therefore resulting in prevention of vision loss. In addition, we also plan to apply the versatile multiplex CRISPR/Cas9 gene editing system to selectively abolish the mutant allele of the RP1 gene by targeting the haplotype of the RP1 gene in a cell culture system, which may provide insights on retinitis pigmentosa 1 treatment regardless of the causal mutations.