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Publication : High-efficiency base editing in the retina in primates and human tissues.

First Author  Muller A Year  2025
Journal  Nat Med Volume  31
Issue  2 Pages  490-501
PubMed ID  39779923 Mgi Jnum  J:362136
Mgi Id  MGI:7869278 Doi  10.1038/s41591-024-03422-8
Citation  Muller A, et al. (2025) High-efficiency base editing in the retina in primates and human tissues. Nat Med 31(2):490-501
abstractText  Stargardt disease is a currently untreatable, inherited neurodegenerative disease that leads to macular degeneration and blindness due to loss-of-function mutations in the ABCA4 gene. We have designed a dual adeno-associated viral vector encoding a split-intein adenine base editor to correct the most common mutation in ABCA4 (c.5882G>A, p.Gly1961Glu). We optimized ABCA4 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.
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