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

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 and Krzysztof Palczewski ()
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Elliot H. Choi: University of California
Susie Suh: University of California
Andrzej T. Foik: Polish Academy of Sciences
Henri Leinonen: University of California
Gregory A. Newby: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Xin D. Gao: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Samagya Banskota: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Thanh Hoang: Johns Hopkins University School of Medicine
Samuel W. Du: University of California
Zhiqian Dong: University of California
Aditya Raguram: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Sajeev Kohli: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Seth Blackshaw: Johns Hopkins University School of Medicine
David C. Lyon: University of California
David R. Liu: Merkin Institute of Transformative Technologies in Healthcare at Broad Institute
Krzysztof Palczewski: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-14

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

Date: 2022
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DOI: 10.1038/s41467-022-29490-3

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