{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:15:28Z","timestamp":1782306928701,"version":"3.54.5"},"posted":{"date-parts":[[2025,7,29]]},"group-title":"Genetic and Genomic Medicine","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    GM1 gangliosidosis, caused by biallelic variants in\n                    <jats:italic>GLB1<\/jats:italic>\n                    , results from deficiency of lysosomal \u03b2-galactosidase, the enzyme primarily responsible for degradation of GM1 ganglioside. This progressive neurodegenerative disease is uniformly fatal with no approved therapies, but preclinical studies utilizing gene therapy have shown promising results.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>This phase 1-2 open label dose escalation study utilized a single intravenous administration of adeno-associated virus serotype 9 (AAV9) encoding \u03b2-galactosidase in the first nine enrolled Type II GM1 gangliosidosis participants. The primary endpoint was safety after 3 years; secondary and exploratory efficacy outcomes included cerebrospinal fluid (CSF) GM1 ganglioside and \u03b2-galactosidase, clinical assessments, and neuroimaging changes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    One serious adverse event was attributed to the vector, i.e., vomiting requiring rehospitalization for IV hydration. Serum aspartate and alanine aminotransferase levels increased following gene transfer but returned to baseline by 18 months. Per protocol analysis found stability in Vineland Expressive Communication and Gross Motor and significant declines in Fine Motor and Receptive Communication. Median CGI-Improvement scores at 2 and 3 years after gene transfer were \u201cminimally improved\u201d or \u201cno change\u201d. CSF \u03b2-galactosidase increased and GM1 ganglioside decreased in all participants. MRI showed improved myelination by differential tractography and declines in cerebral atrophy. MRS showed reduced loss of\n                    <jats:italic>N<\/jats:italic>\n                    -acetylaspartate+\n                    <jats:italic>N<\/jats:italic>\n                    -acetylaspartyl glutamate (NAA) compared with historical controls.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    A single IV infusion of AAV9 encoding \u03b2-galactosidase was well-tolerated among the first nine Type II GM1 gangliosidosis participants. Secondary and exploratory outcomes suggested improvements in biochemical markers and neuroimaging and stabilized or reduced rates of developmental deterioration (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03952637\">NCT03952637<\/jats:ext-link>\n                    ).\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.28.25332074","type":"posted-content","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T04:05:12Z","timestamp":1753848312000},"source":"Crossref","is-referenced-by-count":2,"title":["AAV9 Gene Therapy in GM1 Gangliosidosis Type II: A Phase 1\/2 Trial"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8204-5848","authenticated-orcid":false,"given":"Connor J.","family":"Lewis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Precilla","family":"D\u2019Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean M.","family":"Johnston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T.","family":"Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6878-5199","authenticated-orcid":false,"given":"Cristan","family":"Farmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7347-2170","authenticated-orcid":false,"given":"Eva H.","family":"Baker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Crowell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoliann","family":"Mojica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumaiya","family":"Rahman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Joseph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Hartman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"V\u00e9zina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zenaide","family":"Quezado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad H.","family":"Yousef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Luckett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"Vardar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Salman","family":"Shazeeb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Corti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Blackwood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Coleman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Thurm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"De Boever","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Gahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry J.","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence R.","family":"Flotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuntian","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Gross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5202-4616","authenticated-orcid":false,"given":"Allison M.","family":"Keeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Gray-Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas R.","family":"Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sena-Esteves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia J.","family":"Tifft","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025073102000609000_2025.07.28.25332074v1.1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.734878"},{"key":"2025073102000609000_2025.07.28.25332074v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-018-0315-2"},{"key":"2025073102000609000_2025.07.28.25332074v1.3","doi-asserted-by":"publisher","DOI":"10.1186\/s12881-017-0417-4"},{"key":"2025073102000609000_2025.07.28.25332074v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2020.100676"},{"key":"2025073102000609000_2025.07.28.25332074v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2025.109025"},{"key":"2025073102000609000_2025.07.28.25332074v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.12.432"},{"key":"2025073102000609000_2025.07.28.25332074v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12646"},{"key":"2025073102000609000_2025.07.28.25332074v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab309"},{"key":"2025073102000609000_2025.07.28.25332074v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2019.11.023"},{"key":"2025073102000609000_2025.07.28.25332074v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104627"},{"key":"2025073102000609000_2025.07.28.25332074v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2024.101144"},{"key":"2025073102000609000_2025.07.28.25332074v1.12","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-025-03614-6"},{"key":"2025073102000609000_2025.07.28.25332074v1.13","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf198"},{"key":"2025073102000609000_2025.07.28.25332074v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/jcpt.13733"},{"key":"2025073102000609000_2025.07.28.25332074v1.15","unstructured":"Neurogene. Neurogene Provides Update on NGN-401 Gene Therapy Clinical Trial for Rett Syndrome. November 18, 2024 (https:\/\/ir.neurogene.com\/news-releases\/news-release-details\/neurogene-provides-update-ngn-401-gene-therapy-clinical-trial)."},{"key":"2025073102000609000_2025.07.28.25332074v1.16","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006419"},{"key":"2025073102000609000_2025.07.28.25332074v1.17","unstructured":"Rocket Pharmaceuticals. Rocket Pharmaceuticals Provides Update on Phase 2 Clinical Trial of RP-A501 for Danon Disease. May 27, 2025 (https:\/\/ir.rocketpharma.com\/news-releases\/news-release-details\/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp)."},{"key":"2025073102000609000_2025.07.28.25332074v1.18","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307798"},{"key":"2025073102000609000_2025.07.28.25332074v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2025.05.017"},{"key":"2025073102000609000_2025.07.28.25332074v1.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2407766"},{"key":"2025073102000609000_2025.07.28.25332074v1.21","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2214084"},{"key":"2025073102000609000_2025.07.28.25332074v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01664-4"},{"key":"2025073102000609000_2025.07.28.25332074v1.23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2412392"},{"key":"2025073102000609000_2025.07.28.25332074v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003640"},{"key":"2025073102000609000_2025.07.28.25332074v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06621-3"},{"key":"2025073102000609000_2025.07.28.25332074v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)30374-9"},{"key":"2025073102000609000_2025.07.28.25332074v1.27","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13861"},{"key":"2025073102000609000_2025.07.28.25332074v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv168"},{"key":"2025073102000609000_2025.07.28.25332074v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007733"},{"key":"2025073102000609000_2025.07.28.25332074v1.30","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307952"},{"key":"2025073102000609000_2025.07.28.25332074v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(25)00125-5"},{"key":"2025073102000609000_2025.07.28.25332074v1.32","doi-asserted-by":"publisher","DOI":"10.1126\/science.adm8386"},{"key":"2025073102000609000_2025.07.28.25332074v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2024.101144"},{"key":"2025073102000609000_2025.07.28.25332074v1.34","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1016\/B978-0-444-59565-2.00039-3","article-title":"Gangliosidoses","volume":"113","year":"2013","journal-title":"Handbook of clinical neurology"},{"key":"2025073102000609000_2025.07.28.25332074v1.35","unstructured":"Regier , Debra S. , Cynthia J. Tifft , and Caroline E. Rothermel . \u201cGLB1-related disorders.\u201d (2021)."},{"key":"2025073102000609000_2025.07.28.25332074v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01664-4"},{"key":"2025073102000609000_2025.07.28.25332074v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104627"},{"key":"2025073102000609000_2025.07.28.25332074v1.38","doi-asserted-by":"publisher","DOI":"10.4155\/bio.13.323"},{"key":"2025073102000609000_2025.07.28.25332074v1.39","doi-asserted-by":"publisher","DOI":"10.1177\/22143602251324857"},{"key":"2025073102000609000_2025.07.28.25332074v1.40","unstructured":"Sparrow SS , Cicchetti DV , Saulnier CA . Vineland-3: Vineland adaptive behavior scales. PsychCorp; 2016."},{"key":"2025073102000609000_2025.07.28.25332074v1.41","doi-asserted-by":"publisher","DOI":"10.1080\/20473869.2025.2486428"},{"key":"2025073102000609000_2025.07.28.25332074v1.42","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-022-09474-6"},{"key":"2025073102000609000_2025.07.28.25332074v1.43","doi-asserted-by":"crossref","unstructured":"Bates D , M\u00e4chler M , Bolker B , Walker S. Fitting linear mixed-effects models using lme4. arXiv preprint arXiv:14065823. 2014.","DOI":"10.18637\/jss.v067.i01"},{"key":"2025073102000609000_2025.07.28.25332074v1.44","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v082.i13"},{"key":"2025073102000609000_2025.07.28.25332074v1.45","doi-asserted-by":"crossref","unstructured":"Guy W . ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, Public Health Service, 1976.","DOI":"10.1037\/e591322011-001"},{"issue":"7","key":"2025073102000609000_2025.07.28.25332074v1.46","first-page":"28","article-title":"The clinical global impressions scale: applying a research tool in clinical practice","volume":"4","year":"2007","journal-title":"Psychiatry (Edgmont)"},{"key":"2025073102000609000_2025.07.28.25332074v1.47","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-025-03614-6"},{"key":"2025073102000609000_2025.07.28.25332074v1.48","unstructured":"National Human Genome Research Institute. Natural History of Glycosphingolipid Storage Disorders and Glycoprotein Disorders. ClinicalTrials.gov identifier: NCT00029965 . https:\/\/clinicaltrials.gov\/study\/NCT00029965."},{"key":"2025073102000609000_2025.07.28.25332074v1.49","unstructured":"National Human Genome Research Institute. A Phase 1\/2 Study of Intravenous Gene Transfer with an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis. ClinicalTrials.gov identifier: NCT03952637 . https:\/\/clinicaltrials.gov\/study\/NCT03952637."},{"key":"2025073102000609000_2025.07.28.25332074v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2025.109025"},{"key":"2025073102000609000_2025.07.28.25332074v1.51","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaf198"},{"key":"2025073102000609000_2025.07.28.25332074v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2016.03.001"},{"key":"2025073102000609000_2025.07.28.25332074v1.53","doi-asserted-by":"publisher","DOI":"10.3389\/fninf.2022.862805"},{"key":"2025073102000609000_2025.07.28.25332074v1.54","doi-asserted-by":"publisher","DOI":"10.3390\/neurosci6020031"},{"key":"2025073102000609000_2025.07.28.25332074v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116131"},{"key":"2025073102000609000_2025.07.28.25332074v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2019.116137"},{"key":"2025073102000609000_2025.07.28.25332074v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2015.10.019"},{"key":"2025073102000609000_2025.07.28.25332074v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2004.07.051"},{"key":"2025073102000609000_2025.07.28.25332074v1.59","unstructured":"Dhollander T , Raffelt D , Connelly A . Unsupervised 3-tissue response function estimation from single-shell or multi-shell diffusion MR data without a co-registered T1 image. ISMRM Workshop on Breaking the Barriers of Diffusion MRI, 2016, 5."},{"key":"2025073102000609000_2025.07.28.25332074v1.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2011.09.015"},{"key":"2025073102000609000_2025.07.28.25332074v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2008.10.055"},{"key":"2025073102000609000_2025.07.28.25332074v1.62","doi-asserted-by":"publisher","DOI":"10.1109\/TMI.2010.2045126"},{"key":"2025073102000609000_2025.07.28.25332074v1.63","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.1910300604"},{"issue":"1","key":"2025073102000609000_2025.07.28.25332074v1.64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/jmrb.1993.1055","article-title":"Absolute quantitation of water and metabolites in the human brain","volume":"102","year":"1993","journal-title":"I. Compartments and water. Journal of magnetic resonance, Series B"},{"key":"2025073102000609000_2025.07.28.25332074v1.65","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awh467"},{"issue":"8","key":"2025073102000609000_2025.07.28.25332074v1.66","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1002\/acn3.222","article-title":"Evaluation of disease progression in INCL by MR spectroscopy","volume":"2","year":"2015","journal-title":"Annals of clinical and translational neurology"},{"issue":"3","key":"2025073102000609000_2025.07.28.25332074v1.67","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/jmri.21285","article-title":"Regional apparent metabolite concentrations in young adult brain measured by 1H MR spectroscopy at 3 Tesla","volume":"27","year":"2008","journal-title":"Journal of Magnetic Resonance Imaging: An Official Journal of the International Society for Magnetic Resonance in Medicine"},{"issue":"3","key":"2025073102000609000_2025.07.28.25332074v1.68","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/mrm.10242","article-title":"Rapid method for correction of CSF partial volume in quantitative proton MR spectroscopic imaging","volume":"48","year":"2002","journal-title":"Magnetic Resonance in Medicine: An Official Journal of the International Society for Magnetic Resonance in Medicine"},{"key":"2025073102000609000_2025.07.28.25332074v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/0887-8994(93)90067-M"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.07.28.25332074","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:41:41Z","timestamp":1768509701000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.07.28.25332074"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,29]]},"references-count":69,"URL":"https:\/\/doi.org\/10.1101\/2025.07.28.25332074","relation":{},"subject":[],"published":{"date-parts":[[2025,7,29]]},"subtype":"preprint"}}