Open AccessRestoration of visual function in adult mice with an inherited retinal disease via adenine base editing
Author(s) -
Suk-Hwan Suh,
Elliot H. Choi,
Henri Lein,
Andrzej T. Foik,
Gregory A. Newby,
Wei-Hsi Yeh,
Zhiqian Dong,
Philip D. Kiser,
David C. Lyon,
David R. Liu,
Krzysztof Palczewski
Publication year - 2020
Publication title -
nature biomedical engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.961
H-Index - 56
ISSN - 2157-846X
DOI - 10.1038/s41551-020-00632-6
Subject(s) - indel , biology , point mutation , rpe65 , genetics , nonsense mutation , retinal , dna , mutation , base pair , microbiology and biotechnology , gene , genetic enhancement , biochemistry , missense mutation , genotype , single nucleotide polymorphism
Cytosine base editors and adenine base editors (ABEs) can correct point mutations predictably and independent of Cas9-induced double-stranded DNA breaks (which causes substantial indel formation) and homology-directed repair (which typically leads to low editing efficiency). Here, we show, in adult mice, that a subretinal injection of a lentivirus expressing an ABE and a single-guide RNA targeting a de novo nonsense mutation in the Rpe65 gene corrects the pathogenic mutation with up to 29% efficiency and with minimal formation of indel and off-target mutations, despite the absence of the canonical NGG sequence as a protospacer-adjacent motif. The ABE-treated mice displayed restored RPE65 expression and retinoid isomerase activity, and near-normal levels of retinal and visual functions. Our findings motivate the further testing of ABEs for the treatment of inherited retinal diseases and for the correction of pathological mutations with non-canonical protospacer-adjacent motifs.