Prime Editing Strategy to Install the PRPH2 c.828+1G>A Mutation.

ABSTRACT

Mutations in peripherin 2 (PRPH2) are associated with a spectrum of inherited retinal diseases (IRDs) including retinitis pigmentosa (RP) and macular degeneration. As PRPH2 is localized to cone and rod outer segments, mutations in PRPH2 lead the disorganization or absence of photoreceptor outer segments. Here, we report on a patient with PRPH2-linked RP who exhibited widespread RPE atrophy with a central area of macular atrophy sparing the fovea. In future studies, we plan to model the pathobiology of PRPH2-based RP using induced pluripotent stem cell (iPSC)-derived retinal organoids. To effectively model rare mutations using iPSC-derived retinal organoids, we first require a strategy that can install the desired mutation in healthy wild-type iPSC, which can efficiently generate well-laminated retinal organoids. In this study, we developed an efficient prime editing strategy for the installation of the pathogenic PRPH2 c.828+1 G>A splice-site mutation underlying our patient's disease.