{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T22:34:15Z","timestamp":1784759655580,"version":"3.55.0"},"reference-count":48,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":59,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Division of Intramural Research, NIDDK","award":["1ZIADK056016-17"],"award-info":[{"award-number":["1ZIADK056016-17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,15]]},"abstract":"<jats:p>\n                    Late-onset Tay-Sachs (LOTS) disease is a lysosomal storage disorder most commonly caused by a point mutation (c.805G&gt;A) in the\n                    <jats:italic>HEXA<\/jats:italic>\n                    gene encoding the \u03b1 subunit of the lysosomal enzyme \u03b2-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\n                    <jats:italic>HEXA<\/jats:italic>\n                    c.805G&gt;A mutation. Base editing in fibroblasts from a patient with LOTS successfully converted the pathogenic\n                    <jats:italic>HEXA<\/jats:italic>\n                    c.805A to G and partially restored \u03b2-hexosaminidase activity, with minimal genome-wide off-target editing. We generated a LOTS mouse model in which the mice exhibited decreased \u03b2-hexosaminidase activity, accumulation of GM2 ganglioside in the brain, progressive neurological manifestations, and reduced lifespan. Treatment of LOTS mice with the neurotropic virus AAV-PHP.eB carrying the ABE and an sgRNA targeting the LOTS point mutation partially corrected the c.805G&gt;A mutation in the CNS, significantly increased brain \u03b2-hexosaminidase activity, and substantially reduced GM2 ganglioside accumulation in the brain. Moreover, the therapy delayed symptom onset and significantly extended median lifespan. These findings highlight the potential of base editing as an effective treatment for LOTS and its broader applicability to other lysosomal storage disorders.\n                  <\/jats:p>","DOI":"10.1172\/jci183434","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T12:00:33Z","timestamp":1750161633000},"source":"Crossref","is-referenced-by-count":6,"title":["CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Maria L.","family":"Allende","sequence":"first","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-4350","authenticated-orcid":true,"given":"Mari","family":"Kono","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. Terry","family":"Lee","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha M.","family":"Olmsted","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vienna","family":"Huso","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna Y.","family":"Bakir","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florencia","family":"Pratto","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuiling","family":"Li","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen","family":"Byrnes","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Tuymetova","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongling","family":"Zhu","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3931-1207","authenticated-orcid":true,"given":"Cynthia J.","family":"Tifft","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-1270","authenticated-orcid":true,"given":"Richard L.","family":"Proia","sequence":"additional","affiliation":[{"name":"Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2021.136195"},{"issue":"suppl 1","key":"B2","first-page":"663","article-title":"The GM1 and GM2 gangliosidoses: natural history and progress toward therapy","volume":"13 Suppl 1","author":"Regier","year":"2016","journal-title":"Pediatr Endocrinol Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/01.GIM.0000154300.84107.75"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2023.101014"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21061"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1126\/science.2522679"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.7.2413"},{"issue":"4","key":"B8","first-page":"817","article-title":"Ashkenazi-Jewish and non-Jewish adult GM2 gangliosidosis patients share a common genetic defect","volume":"46","author":"Navon","year":"1990","journal-title":"Am J Hum Genet"},{"issue":"4","key":"B9","first-page":"698","article-title":"Frequency of three Hex A mutant alleles among Jewish and non-Jewish carriers identified in a Tay-Sachs screening program","volume":"47","author":"Paw","year":"1990","journal-title":"Am J Hum Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-018-0059-1"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)43301-1"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)90623-X"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.74.12.5463"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4278"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0055-0"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-170"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.09.012"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01664-4"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.10.011"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4593"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0501-5"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/cpcb.115"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2020.10.003"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109879"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01947-6"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2023.1173200"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.11.004"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0057-5"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.010"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2006.01.006"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50196-X"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)83290-2"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1064924"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-022-00911-4"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1089\/genbio.2022.0015"},{"key":"B36","doi-asserted-by":"crossref","unstructured":"Tsourmas KI, et al. Myeloid-derived \u03b2-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease [preprint]. https:\/\/doi.org\/10.1101\/2024.10.21.619538 Posted on bioRxiv October 22, 2024","DOI":"10.1101\/2024.10.21.619538"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.20.10954"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1126\/science.adm8386"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-018-0025-4"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12596"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.29.17377"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300149R"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2023.100463"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.51067"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4194"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3791\/1787"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/laban0511-155"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0032-3"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/183434\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:56:46Z","timestamp":1779213406000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/183434"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,17]]},"references-count":48,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,6,3]]},"published-print":{"date-parts":[[2025,8,15]]}},"alternative-id":["10.1172\/JCI183434"],"URL":"https:\/\/doi.org\/10.1172\/jci183434","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,17]]},"article-number":"e183434"}}