The Scope of Pathogenic ABCA4 Mutations Targetable by CRISPR DNA Base Editing Systems—A Systematic Review

Journal article

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 split-intein adenine base-editing strategy to correct the most common mutation in ABCA4 (c.5882G>A, p.G1961E). We optimized ABCA4 base editing in human models, including retinal organoids, iPSC-derived retinal pigment epithelial (RPE) cells, as well as adult human retinal- and RPE/choroid explants in vitro. The resulting gene therapy vectors achieved high levels of gene correction in mutation-carrying mice and in non-human primates, with an average editing of 37% of photoreceptors and 73% of RPE cells in vivo. The high editing rates in primates make way for precise and efficient gene editing in other neurodegenerative ocular diseases

Authors: Piotter, E; McClements, ME; MacLaren, RE

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Frontiers Media
• Journal: Frontiers in Genetics
• Volume: 12
• Pages: 814131-814131
• Article number: 814131
• Publication date: 2022-01-27
• DOI: 10.3389/fgene.2021.814131
• EISSN: 1664-8021
• ISSN: 1664-8021
• Language: English
• Keywords: CRISPR; ABCA4; Genetics; Cas9; Frameshift mutation; Mutation; Genome editing; Biology; Computational biology; Gene; Phenotype