{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T16:07:31Z","timestamp":1787933251735,"version":"build-2784847793"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Tay-Sachs and Allied Diseases Association","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"DOI":"10.13039\/100007920","name":"UMass Chan Medical School","doi-asserted-by":"crossref","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100007920","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Scott-Ritchey Research Center","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"NIH","award":["K08NS096219"],"award-info":[{"award-number":["K08NS096219"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:p>\n                    Tay-Sachs disease (TSD) and Sandhoff disease are fatal neurodegenerative diseases without an effective therapy that are caused by mutations in the\n                    <jats:italic>HEXA<\/jats:italic>\n                    and\n                    <jats:italic>HEXB<\/jats:italic>\n                    genes, respectively. Together they encode the heterodimeric isozyme of hexosaminidase, hexosaminidase A (HexA), that degrades GM2 ganglioside. This report describes a 5-year-long study using a bidirectional adeno-associated virus 9 (AAV9) vector (AAV9-Bic_HexA\/HexB) encoding both\n                    <jats:italic>HEXA<\/jats:italic>\n                    and\n                    <jats:italic>HEXB<\/jats:italic>\n                    in the TSD sheep model. Bidirectional AAV9 was delivered i.v. or through various cerebrospinal fluid (CSF) delivery routes: intracerebroventricular (ICV), cisterna magna (CM), and lumbar intrathecal space (LIT). The longest survival and best distribution were achieved by multipoint CSF delivery (combined CM, ICV, and LIT) with treated animals that survived up to 5 years of age (untreated animals with TSD die after ~9 months). Extension in survival was accompanied by lasting improvement in neurological examination and maze testing. Improvement in biomarkers of efficacy, including MRI, magnetic resonance spectroscopy, diffusion tensor imaging, and CSF levels of GM2 ganglioside and HexA activity, was evident. Postmortem assessments showed broad HexA distribution, GM2 ganglioside clearance, and vector genome distribution, especially in deep brain structures. Therapeutic efficacy documented in this study supports translation of bidirectional vector and multipoint CSF delivery to a clinical trial in patients with TSD and Sandhoff disease.\n                  <\/jats:p>","DOI":"10.1172\/jci182942","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T16:01:18Z","timestamp":1759248078000},"source":"Crossref","is-referenced-by-count":3,"title":["Five-year analysis of efficacy and safety of a bidirectional AAV gene therapy in Tay-Sachs sheep"],"prefix":"10.1172","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7914-4733","authenticated-orcid":true,"given":"Toloo","family":"Taghian","sequence":"first","affiliation":[{"name":"Department of Radiology and"},{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, 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