biostudies-literatureAllende MLIntramural NIH HHSe183434https://www.ebi.ac.uk/biostudies/studies/S-EPMC12352896biostudies-literatureUnknown135(16)Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with an sgRNA to correct the HEXA c.805G>A mutation. Base editing in fibroblasts from a patient with LOTS successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurologicThe Journal of clinical investigationCNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice.PMC12352896ZIA DK056016Lee YTByrnes CLi CBakir JYAllende MLZhu HOlmsted SMTuymetova GPratto FProia RLKono MTifft CJHuso VfalseCNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice.Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G>A) in the HEXA gene encoding the α subunit of the lysosomal enzyme β-hexosaminidase A. LOTS manifests as a range of gradually worsening neurological symptoms beginning in young adulthood. Here, we explored the efficacy of an adenine base editor (ABE) programmed with an sgRNA to correct the HEXA c.805G>A mutation. Base editing in fibroblasts from a patient with LOTS successfully converted the pathogenic HEXA c.805A to G and partially restored β-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased β-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurologic2025-01-01T00:00:00Z2025 Aug2026-05-29T16:34:25.037Z2026-04-08T05:24:47.031ZS-EPMC123528964052643710.1172/JCI183434