{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:28:46Z","timestamp":1791808126723,"version":"4.3.4"},"reference-count":60,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U01NS064096"],"award-info":[{"award-number":["U01NS064096"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>GM2 gangliosidosis is usually fatal by 5\u2009years of age in its 2 major subtypes, Tay\u2010Sachs and Sandhoff disease. First reported in 1881, GM2 gangliosidosis has no effective treatment today, and children succumb to the disease after a protracted neurodegenerative course and semi\u2010vegetative state. This study seeks to further develop adeno\u2010associated virus (AAV) gene therapy for human translation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cats with Sandhoff disease were treated by intracranial injection of vectors expressing feline \u03b2\u2010N\u2010acetylhexosaminidase, the enzyme deficient in GM2 gangliosidosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hexosaminidase activity throughout the brain and spinal cord was above normal after treatment, with highest activities at the injection sites (thalamus and deep cerebellar nuclei). Ganglioside storage was reduced throughout the brain and spinal cord, with near complete clearance in many regions. While untreated cats with Sandhoff disease lived for 4.4\u2009\u00b1\u20090.6\u2009months, AAV\u2010treated cats lived to 19.1\u2009\u00b1\u20098.6\u2009months, and 3 of 9 cats lived &gt;21\u2009months. Correction of the central nervous system was so effective that significant increases in lifespan led to the emergence of otherwise subclinical peripheral disease, including megacolon, enlarged stomach and urinary bladder, soft tissue spinal cord compression, and patellar luxation. Throughout the gastrointestinal tract, neurons of the myenteric and submucosal plexuses developed profound pathology, demonstrating that the enteric nervous system was inadequately treated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>The vector formulation in the current study effectively treats neuropathology in feline Sandhoff disease, but whole\u2010body targeting will be an important consideration in next\u2010generation approaches. 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