{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T22:49:05Z","timestamp":1780613345336,"version":"3.54.1"},"reference-count":76,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T00:00:00Z","timestamp":1684886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009056","name":"GLYCONET","doi-asserted-by":"publisher","award":["ND06"],"award-info":[{"award-number":["ND06"]}],"id":[{"id":"10.13039\/501100009056","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009056","name":"GLYCONET","doi-asserted-by":"publisher","award":["1079923"],"award-info":[{"award-number":["1079923"]}],"id":[{"id":"10.13039\/501100009056","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CURE TAY-SACHS FOUNDATION","award":["ND06"],"award-info":[{"award-number":["ND06"]}]},{"name":"CURE TAY-SACHS FOUNDATION","award":["1079923"],"award-info":[{"award-number":["1079923"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>GM2 gangliosidosis is a group of genetic disorders that result in the accumulation of GM2 ganglioside (GM2) in brain cells, leading to progressive central nervous system (CNS) atrophy and premature death in patients. AB-variant GM2 gangliosidosis (ABGM2) arises from loss-of-function mutations in the GM2 activator protein (GM2AP), which is essential for the breakdown of GM2 in a key catabolic pathway required for CNS lipid homeostasis. In this study, we show that intrathecal delivery of self-complementary adeno-associated virus serotype-9 (scAAV9) harbouring a functional human GM2A transgene (scAAV9.hGM2A) can prevent GM2 accumulation in in GM2AP-deficient mice (Gm2a\u2212\/\u2212 mice). Additionally, scAAV9.hGM2A efficiently distributes to all tested regions of the CNS within 14 weeks post-injection and remains detectable for the lifespan of these animals (up to 104 weeks). Remarkably, GM2AP expression from the transgene scales with increasing doses of scAAV9.hGM2A (0.5, 1.0 and 2.0 \u00d7 1011 vector genomes (vg) per mouse), and this correlates with dose-dependent correction of GM2 accumulation in the brain. No severe adverse events were observed, and comorbidities in treated mice were comparable to those in disease-free cohorts. Lastly, all doses yielded corrective outcomes. These data indicate that scAAV9.hGM2A treatment is relatively non-toxic and tolerable, and biochemically corrects GM2 accumulation in the CNS\u2014the main cause of morbidity and mortality in patients with ABGM2. Importantly, these results constitute proof-of-principle for treating ABGM2 with scAAV9.hGM2A by means of a single intrathecal administration and establish a foundation for future preclinical research.<\/jats:p>","DOI":"10.3390\/ijms24119217","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T02:58:48Z","timestamp":1684983528000},"page":"9217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Biochemical Correction of GM2 Ganglioside Accumulation in AB-Variant GM2 Gangliosidosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2306-2661","authenticated-orcid":false,"given":"Natalie M.","family":"Deschenes","sequence":"first","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilyn","family":"Cheng","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex E.","family":"Ryckman","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna M.","family":"Quinville","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prem","family":"Khanal","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 2V7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 2V7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhilin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waheed","family":"Sangrar","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6240-8621","authenticated-orcid":false,"given":"Steven J.","family":"Gray","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdeep S.","family":"Walia","sequence":"additional","affiliation":[{"name":"Centre for Neuroscience Studies, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"},{"name":"Department of Pediatrics, Queen\u2019s University, Kingston, ON K7L 2V7, Canada"},{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1139\/o80-038","article-title":"The subunit and polypeptide structure of hexosaminidases from human placenta","volume":"58","author":"Mahuran","year":"1980","journal-title":"Can. 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