{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:53:44Z","timestamp":1791438824310,"version":"4.3.3"},"reference-count":43,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014440","name":"Gobierno de Espa\u00f1a Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007920","name":"University of Massachusetts Medical School","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007920","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Molecular Therapy Nucleic Acids"],"published-print":{"date-parts":[[2026,6]]},"DOI":"10.1016\/j.omtn.2026.102899","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:08:32Z","timestamp":1773335312000},"page":"102899","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":0,"title":["Orthogonal characterization of rAAV reveals vector attributes that drive ITR repair, self-complementary genome formation, and transgene expression"],"prefix":"10.1016","volume":"37","author":[{"given":"Carla","family":"Llinares","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk","family":"Namkung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Yip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1frica","family":"Vales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Olag\u00fce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itsaso","family":"Maule\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Isola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedram","family":"Moeini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Gonz\u00e1lez-Aseguinolaza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip W.L.","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1582-7196","authenticated-orcid":false,"given":"Carmen","family":"Unzu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.omtn.2026.102899_bib1","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/s41573-019-0012-9","article-title":"Adeno-associated virus vector as a platform for gene therapy delivery","volume":"18","author":"Wang","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.omtn.2026.102899_bib2","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.omtn.2026.102899_bib3","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1016\/j.ymthe.2022.09.015","article-title":"AAV vectors: The Rubik\u2019s cube of human gene therapy","volume":"30","author":"Pupo","year":"2022","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib4","doi-asserted-by":"crossref","first-page":"6466","DOI":"10.1073\/pnas.81.20.6466","article-title":"Use of adeno-associated virus as a mammalian DNA cloning vector: transduction of neomycin resistance into mammalian tissue culture cells","volume":"81","author":"Hermonat","year":"1984","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"10.1016\/j.omtn.2026.102899_bib5","first-page":"928","article-title":"Adeno-associated virus 2-mediated gene transfer in murine hematopoietic progenitor cells","volume":"21","author":"Zhou","year":"1993","journal-title":"Exp. Hematol."},{"key":"10.1016\/j.omtn.2026.102899_bib6","doi-asserted-by":"crossref","DOI":"10.1002\/biot.201600193","article-title":"Manufacturing of recombinant adeno-associated viruses using mammalian expression platforms","volume":"12","author":"Robert","year":"2017","journal-title":"Biotechnol. J."},{"key":"10.1016\/j.omtn.2026.102899_bib7","doi-asserted-by":"crossref","first-page":"3227","DOI":"10.1128\/jvi.70.5.3227-3234.1996","article-title":"Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors","volume":"70","author":"Ferrari","year":"1996","journal-title":"J. Virol."},{"key":"10.1016\/j.omtn.2026.102899_bib8","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1128\/jvi.70.1.520-532.1996","article-title":"Transduction with recombinant adeno-associated virus for gene therapy is limited by leading-strand synthesis","volume":"70","author":"Fisher","year":"1996","journal-title":"J. Virol."},{"key":"10.1016\/j.omtn.2026.102899_bib9","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/sj.gt.3301514","article-title":"Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis","volume":"8","author":"McCarty","year":"2001","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib10","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/sj.gt.3302134","article-title":"Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo","volume":"10","author":"McCarty","year":"2003","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib11","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1128\/jvi.71.2.941-948.1997","article-title":"A novel 165-base-pair terminal repeat sequence is the sole cis requirement for the adeno-associated virus life cycle","volume":"71","author":"Xiao","year":"1997","journal-title":"J. Virol."},{"key":"10.1016\/j.omtn.2026.102899_bib12","doi-asserted-by":"crossref","first-page":"6096","DOI":"10.1128\/jvi.67.10.6096-6104.1993","article-title":"Features of the adeno-associated virus origin involved in substrate recognition by the viral Rep protein","volume":"67","author":"Snyder","year":"1993","journal-title":"J. Virol."},{"key":"10.1016\/j.omtn.2026.102899_bib13","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1038\/mt.2008.171","article-title":"Self-complementary AAV vectors; advances and applications","volume":"16","author":"McCarty","year":"2008","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib14","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1089\/hum.2006.088","article-title":"Self-complementary recombinant adeno-associated viral vectors: packaging capacity and the role of rep proteins in vector purity","volume":"18","author":"Wu","year":"2007","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib15","doi-asserted-by":"crossref","first-page":"5432","DOI":"10.1038\/s41598-017-04054-4","article-title":"Deletion of the B-B\u2019 and C-C\u2019 regions of inverted terminal repeats reduces rAAV productivity but increases transgene expression","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci. Rep."},{"key":"10.1016\/j.omtn.2026.102899_bib16","doi-asserted-by":"crossref","DOI":"10.1016\/j.omtm.2024.101206","article-title":"A novel class of self-complementary AAV vectors with multiple advantages based on cceAAV lacking mutant ITR","volume":"32","author":"Zhang","year":"2024","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtn.2026.102899_bib17","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1038\/nature04791","article-title":"Fatality in mice due to oversaturation of cellular microRNA\/short hairpin RNA pathways","volume":"441","author":"Grimm","year":"2006","journal-title":"Nature"},{"key":"10.1016\/j.omtn.2026.102899_bib18","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/s41434-024-00444-2","article-title":"Analytical characterization of full, intermediate, and empty AAV capsids","volume":"31","author":"McColl-Carboni","year":"2024","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib19","doi-asserted-by":"crossref","DOI":"10.1016\/j.omtm.2023.101148","article-title":"Fast HPLC-based affinity method to determine capsid titer and full\/empty ratio of adeno-associated viral vectors","volume":"31","author":"Heckel","year":"2023","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtn.2026.102899_bib20","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1016\/j.omtm.2021.08.009","article-title":"Comparison of analytical techniques to quantitate the capsid content of adeno-associated viral vectors","volume":"23","author":"Werle","year":"2021","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtn.2026.102899_bib21","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.omtm.2017.11.007","article-title":"Emerging Issues in AAV-Mediated In Vivo Gene Therapy","volume":"8","author":"Colella","year":"2018","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"10.1016\/j.omtn.2026.102899_bib22","doi-asserted-by":"crossref","first-page":"80","DOI":"10.3390\/biomedicines2010080","article-title":"Product-Related Impurities in Clinical-Grade Recombinant AAV Vectors: Characterization and Risk Assessment","volume":"2","author":"Wright","year":"2014","journal-title":"Biomedicines"},{"key":"10.1016\/j.omtn.2026.102899_bib23","article-title":"Cryptic resolution sites in the vector plasmid lead to the heterogeneities in the rAAV vectors","volume":"95","author":"Zhang","year":"2023","journal-title":"J. Med. Virol."},{"key":"10.1016\/j.omtn.2026.102899_bib24","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/nature12875","article-title":"Selection and evaluation of clinically relevant AAV variants in a xenograft liver model","volume":"506","author":"Lisowski","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.omtn.2026.102899_bib25","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.1038\/s41467-023-38106-3","article-title":"The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner","volume":"14","author":"Gonzalez-Sandoval","year":"2023","journal-title":"Nat. Commun."},{"key":"10.1016\/j.omtn.2026.102899_bib26","doi-asserted-by":"crossref","first-page":"3194","DOI":"10.1016\/S0021-9258(19)85870-2","article-title":"Molecular structure of adeno-associated virus variant DNA","volume":"255","author":"de la Maza","year":"1980","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.omtn.2026.102899_bib27","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s44321-023-00008-8","article-title":"Efficient and safe therapeutic use of paired Cas9-nickases for primary hyperoxaluria type 1","volume":"16","author":"Torella","year":"2024","journal-title":"EMBO Mol. Med."},{"key":"10.1016\/j.omtn.2026.102899_bib28","doi-asserted-by":"crossref","first-page":"788","DOI":"10.3390\/v13050788","article-title":"AAV-HDV: An Attractive Platform for the In Vivo Study of HDV Biology and the Mechanism of Disease Pathogenesis","volume":"13","author":"Maestro","year":"2021","journal-title":"Viruses"},{"key":"10.1016\/j.omtn.2026.102899_bib29","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1016\/j.ymthe.2017.03.028","article-title":"Short DNA Hairpins Compromise Recombinant Adeno-Associated Virus Genome Homogeneity","volume":"25","author":"Xie","year":"2017","journal-title":"Mol. Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib30","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/s41591-025-04073-z","article-title":"Contaminating plasmid sequences and disrupted vector genomes in the liver following adeno-associated virus gene therapy","volume":"32","author":"Buddle","year":"2026","journal-title":"Nat. Med."},{"key":"10.1016\/j.omtn.2026.102899_bib31","doi-asserted-by":"crossref","DOI":"10.3389\/fmed.2023.1106085","article-title":"AAV- based vector improvements unrelated to capsid protein modification","volume":"10","author":"Shitik","year":"2023","journal-title":"Front. Med."},{"key":"10.1016\/j.omtn.2026.102899_bib32","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1089\/hum.2019.274","article-title":"Adeno-Associated Virus Serotype-Specific Inverted Terminal Repeat Sequence Role in Vector Transgene Expression","volume":"31","author":"Earley","year":"2020","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib33","article-title":"A Comprehensive Study of the Effects by Sequence Truncation within Inverted Terminal Repeats (ITRs) on the Productivity, Genome Packaging, and Potency of AAV Vectors","volume":"12","author":"Chen","year":"2024","journal-title":"Microorganisms"},{"key":"10.1016\/j.omtn.2026.102899_bib34","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/0092-8674(83)90342-2","article-title":"Rescue of adeno-associated virus from recombinant plasmids: gene correction within the terminal repeats of AAV","volume":"33","author":"Samulski","year":"1983","journal-title":"Cell"},{"key":"10.1016\/j.omtn.2026.102899_bib35","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1474-4422(21)00001-6","article-title":"Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial","volume":"20","author":"Day","year":"2021","journal-title":"Lancet Neurol."},{"key":"10.1016\/j.omtn.2026.102899_bib36","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/sj.gt.3300938","article-title":"Recombinant adeno-associated virus purification using novel methods improves infectious titer and yield","volume":"6","author":"Zolotukhin","year":"1999","journal-title":"Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib37","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1089\/hum.2022.050","article-title":"Human and Insect Cell-Produced Recombinant Adeno-Associated Viruses Show Differences in Genome Heterogeneity","volume":"33","author":"Tran","year":"2022","journal-title":"Hum. Gene Ther."},{"key":"10.1016\/j.omtn.2026.102899_bib38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0140829","article-title":"Genomics Virtual Laboratory: A Practical Bioinformatics Workbench for the Cloud","volume":"10","author":"Afgan","year":"2015","journal-title":"PLoS One"},{"key":"10.1016\/j.omtn.2026.102899_bib39","first-page":"19.10.1","article-title":"Galaxy: a web-based genome analysis tool for experimentalists","volume":"19","author":"Blankenberg","year":"2010","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"10.1016\/j.omtn.2026.102899_bib40","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1101\/gr.4086505","article-title":"Galaxy: a platform for interactive large-scale genome analysis","volume":"15","author":"Giardine","year":"2005","journal-title":"Genome Res."},{"key":"10.1016\/j.omtn.2026.102899_bib41","doi-asserted-by":"crossref","first-page":"R86","DOI":"10.1186\/gb-2010-11-8-r86","article-title":"Galaxy: a comprehensive approach for supporting accessible, reproducible, and transparent computational research in the life sciences","volume":"11","author":"Goecks","year":"2010","journal-title":"Genome Biol."},{"key":"10.1016\/j.omtn.2026.102899_bib42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"10.1016\/j.omtn.2026.102899_bib43","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open-source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Molecular Therapy Nucleic Acids"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2162253126000703?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2162253126000703?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:21:06Z","timestamp":1791436866000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2162253126000703"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6]]},"references-count":43,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["S2162253126000703"],"URL":"https:\/\/doi.org\/10.1016\/j.omtn.2026.102899","relation":{},"ISSN":["2162-2531"],"issn-type":[{"value":"2162-2531","type":"print"}],"subject":[],"published":{"date-parts":[[2026,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Orthogonal characterization of rAAV reveals vector attributes that drive ITR repair, self-complementary genome formation, and transgene expression","name":"articletitle","label":"Article Title"},{"value":"Molecular Therapy Nucleic Acids","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.omtn.2026.102899","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Author(s). Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.","name":"copyright","label":"Copyright"}],"article-number":"102899"}}