In vivo base editing rescues cone photoreceptors in a mouse model of early-onset inherited retinal degeneration

• DOI: 10.1038/s41467-022-29490-3
• Publication Date: 2022-04-05T10:12:26Z
• Authors: Elliot H. Choi; Susie Suh; Andrzej T. Foik; Henri Leinonen; Gregory A. Newby; Xin D. Gao; Samagya Banskota; Thanh Hoang; Samuel W. Du; Zhiqian Dong; Aditya Raguram; Sajeev Kohli; Seth Blackshaw; David C. Lyon; David R. Liu; Krzysztof Palczewski
• Keywords: RPE65; Visual phototransduction; Electroretinography

Leber congenital amaurosis (LCA) is the most common cause of inherited retinal degeneration in children. LCA patients with RPE65 mutations show accelerated cone photoreceptor dysfunction and death, resulting early visual impairment. It therefore crucial to develop a robust therapy that not only compensates for lost function but also protects photoreceptors from further degeneration. Here, we vivo correction an Rpe65 mutation by adenine base editor (ABE) prolongs survival cones mouse model. In vitro screening ABEs sgRNAs enables identification variant enhances efficiency. Subretinal delivery ABE sgRNA corrects up 40% transcripts, restores cone-mediated function, preserves mice. Single-cell RNA-seq reveals upregulation genes associated phototransduction survival. Our findings demonstrate editing as potential gene confers long-lasting protection.