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We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in <jats:italic>ABCA4<\/jats:italic> (c.5882G&gt;A, p.Gly1961Glu). We optimized <jats:italic>ABCA4<\/jats:italic> base editing in human models, including retinal organoids, induced pluripotent stem cell-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal explants and RPE\/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in female nonhuman primates, with average editing of 75% of cones and 87% of RPE cells in vivo, which has the potential to translate to a clinical benefit. No off-target editing was detectable in human retinal explants and RPE\/choroid explants. The high editing rates in primates show promise for efficient gene editing in other ocular diseases that are targetable by base editing.<\/jats:p>","DOI":"10.1038\/s41591-024-03422-8","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T10:08:13Z","timestamp":1736330893000},"page":"490-501","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["High-efficiency base editing in the retina in primates and human 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Beam Therapeutics has filed a patent based on some of this work. H.P.N.S. is member of the Scientific Advisory Board of: Boehringer Ingelheim, Droia NV, Janssen Research & Development (Johnson & Johnson) and Okuvision and Tenpoint Therapeutics. H.P.N.S. is a member of the Data Monitoring and Safety Board\/Committee of Belite Bio (DRAGON trial, ; LBS-008-CT02, ), F. Hoffmann-La Roche (VELODROME trial, ; DIAGRID trial, ; HUTONG trial) and ViGeneron (protocol no. VG901-2021-A) and a member of the Steering Committee of Novo Nordisk (FOCUS trial; ). B.R. is a consultant of SpliceBio. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}