{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T01:48:30Z","timestamp":1793152110258,"version":"4.5.0"},"reference-count":46,"publisher":"Elsevier BV","issue":"4","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T00:00:00Z","timestamp":1758844800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018787","name":"Novartis Pharma AG","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018787","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008792","name":"Novartis Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008792","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Therapy Methods & Clinical Development"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1016\/j.omtm.2025.101602","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T07:52:17Z","timestamp":1759305137000},"page":"101602","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impact of pre-existing immunity on safety and biodistribution of a single AAV9 vector intrathecal injection in cynomolgus monkeys"],"prefix":"10.1016","volume":"33","author":[{"given":"Maria","family":"Vono","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony del","family":"Rio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Magdaleno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie R.","family":"Loll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip","family":"Jarvis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Kikkawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Mansfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fraser","family":"McBlane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhu P.","family":"Sirivelu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatih","family":"Ozsolak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Brees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloise","family":"Hudry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina","family":"Rubic-Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis Fonyuy","family":"Tukov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7253-5458","authenticated-orcid":false,"given":"Guanrong","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.omtm.2025.101602_bib1","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1126\/science.149.3685.754","article-title":"Adenovirus-associated defective virus particles","volume":"149","author":"Atchison","year":"1965","journal-title":"Science"},{"key":"10.1016\/j.omtm.2025.101602_bib2","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1016\/j.ymthe.2022.09.015","article-title":"AAV vectors: The Rubik's cube of human gene therapy","volume":"30","author":"Pupo","year":"2022","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib3","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.coviro.2014.07.008","article-title":"Adeno-associated virus: Fit to serve","volume":"8","author":"Zinn","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"10.1016\/j.omtm.2025.101602_bib4","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/hum.2015.025","article-title":"Adeno-associated virus at 50: A golden anniversary of discovery, research, and gene therapy success--a personal perspective","volume":"26","author":"Hastie","year":"2015","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib5","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3389\/fimmu.2020.00670","article-title":"Human immune responses to adeno-associated virus (AAV) vectors","volume":"11","author":"Ronzitti","year":"2020","journal-title":"Front. Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib6","doi-asserted-by":"crossref","DOI":"10.1016\/j.pharmthera.2019.107453","article-title":"Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery","volume":"207","author":"Nidetz","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib7","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.ymthe.2019.12.010","article-title":"AAV vector immunogenicity in humans: A long journey to successful gene transfer","volume":"28","author":"Costa Verdera","year":"2020","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib8","doi-asserted-by":"crossref","DOI":"10.1016\/j.cellimm.2018.03.004","article-title":"Prevalence and long-term monitoring of humoral immunity against adeno-associated virus in Duchenne Muscular Dystrophy patients","volume":"342","author":"Leborgne","year":"2019","journal-title":"Cell. Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib9","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.omtm.2019.05.014","article-title":"Prevalence of anti-adeno-associated virus immune responses in international cohorts of healthy donors","volume":"14","author":"Kruzik","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib10","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1089\/hum.2023.225","article-title":"Prevalence study of cellular capsid-specific immune responses to AAV2, 4, 5, 8, 9, and rh10 in healthy donors","volume":"35","author":"Xicluna","year":"2024","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib11","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1086\/595830","article-title":"Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses","volume":"199","author":"Calcedo","year":"2009","journal-title":"J. Infect. Dis."},{"key":"10.1016\/j.omtm.2025.101602_bib12","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1089\/hum.2009.182","article-title":"Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors","volume":"21","author":"Boutin","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib13","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.ymthe.2020.01.001","article-title":"Immune responses to viral gene therapy vectors","volume":"28","author":"Shirley","year":"2020","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib14","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.omtm.2022.02.011","article-title":"Testing preexisting antibodies prior to AAV gene transfer therapy: rationale, lessons and future considerations","volume":"25","author":"Mendell","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib15","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.omtm.2019.04.004","article-title":"Threshold for pre-existing antibody levels limiting transduction efficiency of systemic rAAV9 gene delivery: Relevance for translation","volume":"13","author":"Meadows","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib16","doi-asserted-by":"crossref","first-page":"2357","DOI":"10.1056\/NEJMoa1108046","article-title":"Adenovirus-associated virus vector-mediated gene transfer in hemophilia B","volume":"365","author":"Nathwani","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.omtm.2025.101602_bib17","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/mt.2013.244","article-title":"Plasmapheresis eliminates the negative impact of AAV antibodies on microdystrophin gene expression following vascular delivery","volume":"22","author":"Chicoine","year":"2014","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib18","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1001\/jamaneurol.2020.1484","article-title":"Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne Muscular Dystrophy: A nonrandomized controlled trial","volume":"77","author":"Mendell","year":"2020","journal-title":"JAMA Neurol."},{"key":"10.1016\/j.omtm.2025.101602_bib19","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1056\/NEJMoa2302982","article-title":"Gene therapy with fidanacogene elaparvovec in adults with hemophilia B","volume":"391","author":"Cuker","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.omtm.2025.101602_bib20","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1208\/s12248-021-00628-3","article-title":"Evaluation of the humoral response to adeno-associated virus-based gene therapy modalities using total antibody assays","volume":"23","author":"Gorovits","year":"2021","journal-title":"AAPS J."},{"key":"10.1016\/j.omtm.2025.101602_bib21","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.omtm.2022.07.018","article-title":"Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper","volume":"26","author":"Yang","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib22","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1080\/19420862.2018.1473910","article-title":"Antibody pharmacokinetics in rat brain determined using microdialysis","volume":"10","author":"Chang","year":"2018","journal-title":"MAbs"},{"key":"10.1016\/j.omtm.2025.101602_bib23","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1172\/JCI66778","article-title":"Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy","volume":"123","author":"Haurigot","year":"2013","journal-title":"J. Clin. Investig."},{"key":"10.1016\/j.omtm.2025.101602_bib24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.omtm.2019.05.009","article-title":"Therapeutic hFIX activity achieved after single AAV5-hFIX treatment in hemophilia B patients and NHPs with pre-existing anti-AAV5 NABs","volume":"14","author":"Majowicz","year":"2019","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib25","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1080\/19420862.2017.1345834","article-title":"Pharmacokinetics of an intracerebroventricularly administered antibody in rats","volume":"9","author":"Noguchi","year":"2017","journal-title":"MAbs"},{"key":"10.1016\/j.omtm.2025.101602_bib26","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1038\/gt.2011.130","article-title":"Robust spinal motor neuron transduction following intrathecal delivery of AAV9 in pigs","volume":"19","author":"Federici","year":"2012","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib27","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/gt.2012.101","article-title":"Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates","volume":"20","author":"Gray","year":"2013","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib28","doi-asserted-by":"crossref","DOI":"10.1038\/mtm.2014.51","article-title":"Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna","volume":"1","author":"Hinderer","year":"2014","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib29","doi-asserted-by":"crossref","DOI":"10.1016\/j.omtm.2024.101371","article-title":"Comparative assessment of the transduction efficiency and safety associated with the delivery of AAV9-GFP vector via lumbar puncture to cynomolgus macaques with and without anti-AAV9 pre-existing antibodies","volume":"32","author":"Guibinga","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib30","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/mt.2009.245","article-title":"The pleiotropic effects of natural AAV infections on liver-directed gene transfer in macaques","volume":"18","author":"Wang","year":"2010","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib31","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1128\/CVI.05107-11","article-title":"Adeno-associated virus antibody profiles in newborns, children, and adolescents","volume":"18","author":"Calcedo","year":"2011","journal-title":"Clin. Vaccine Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib32","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-020-0911-7","article-title":"IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies","volume":"26","author":"Leborgne","year":"2020","journal-title":"Nat. Med."},{"key":"10.1016\/j.omtm.2025.101602_bib33","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/jca.22069","article-title":"Efficient removal of antibodies to adeno-associated viruses by immunoadsorption","volume":"38","author":"Boedecker-Lips","year":"2023","journal-title":"J. Clin. Apher."},{"key":"10.1016\/j.omtm.2025.101602_bib34","doi-asserted-by":"crossref","DOI":"10.1212\/WNL.0000000000213899","article-title":"Reduction of preexisting AAV9 antibody titers before onasemnogene abeparvovec administration in twins with spinal muscular atrophy","volume":"105","author":"Nelson","year":"2025","journal-title":"Neurology"},{"key":"10.1016\/j.omtm.2025.101602_bib35","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1089\/hum.2011.031","article-title":"Impact of pre-existing immunity on gene transfer to nonhuman primate liver with adeno-associated virus 8 vectors","volume":"22","author":"Wang","year":"2011","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib36","doi-asserted-by":"crossref","first-page":"6323","DOI":"10.1016\/j.vaccine.2016.10.053","article-title":"Intramuscular administration of AAV overcomes pre-existing neutralizing antibodies in rhesus macaques","volume":"34","author":"Greig","year":"2016","journal-title":"Vaccine"},{"key":"10.1016\/j.omtm.2025.101602_bib37","doi-asserted-by":"crossref","DOI":"10.3390\/ijms18061249","article-title":"Emerging role of the spleen in the pharmacokinetics of monoclonal antibodies, nanoparticles and exosomes","volume":"18","author":"Cataldi","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"10.1016\/j.omtm.2025.101602_bib38","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1038\/s41590-020-0672-y","article-title":"Remodeling of light and dark zone follicular dendritic cells governs germinal center responses","volume":"21","author":"Pikor","year":"2020","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib39","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.omtm.2020.08.006","article-title":"High-resolution histological landscape of AAV DNA distribution in cellular compartments and tissues following local and systemic injection","volume":"18","author":"Zhao","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtm.2025.101602_bib40","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1146\/annurev-immunol-120419-022408","article-title":"Germinal centers","volume":"40","author":"Victora","year":"2022","journal-title":"Annu. Rev. Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib41","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1089\/hum.2020.113","article-title":"Gene transfer in adeno-associated virus seropositive rhesus macaques following rapamycin treatment and subcutaneous delivery of AAV6, but not retargeted AAV6 vectors","volume":"32","author":"Stone","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib42","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.999021","article-title":"Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood","volume":"13","author":"Smith","year":"2022","journal-title":"Front. Immunol."},{"key":"10.1016\/j.omtm.2025.101602_bib43","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1089\/hum.2023.018","article-title":"Complement activation by adeno-associated virus-neutralizing antibody complexes","volume":"34","author":"West","year":"2023","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtm.2025.101602_bib44","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1056\/NEJMoa1708483","article-title":"AAV5-Factor VIII gene transfer in severe hemophilia A","volume":"377","author":"Rangarajan","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.omtm.2025.101602_bib45","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1056\/NEJMoa2307952","article-title":"Intrathecal gene therapy for giant axonal neuropathy","volume":"390","author":"Bharucha-Goebel","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.omtm.2025.101602_bib46","article-title":"Enhanced detection of antigen-specific T cells by a multiplexed AIM assay","volume":"4","author":"Lemieux","year":"2024","journal-title":"Cell Rep. Methods"}],"updated-by":[{"DOI":"10.1016\/j.omta.2026.201731","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000}}],"container-title":["Molecular Therapy Methods & Clinical Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2329050125001974?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2329050125001974?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T20:34:25Z","timestamp":1776198865000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2329050125001974"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":46,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["S2329050125001974"],"URL":"https:\/\/doi.org\/10.1016\/j.omtm.2025.101602","relation":{},"ISSN":["2329-0501"],"issn-type":[{"value":"2329-0501","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Impact of pre-existing immunity on safety and biodistribution of a single AAV9 vector intrathecal injection in cynomolgus monkeys","name":"articletitle","label":"Article Title"},{"value":"Molecular Therapy Methods & Clinical Development","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.omtm.2025.101602","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 The Author(s). Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.","name":"copyright","label":"Copyright"}],"article-number":"101602"}}