{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:06:31Z","timestamp":1789070791698,"version":"build-2803163510"},"reference-count":35,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,6]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male\u00a0= 4, hemizygous; and female\u00a0= 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e\u22124 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023022589","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T19:57:35Z","timestamp":1709841455000},"page":"2373-2385","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":28,"title":["Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7808-3462","authenticated-orcid":false,"given":"Paul","family":"Batty","sequence":"first","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"},{"name":"2Department of Haematology, Cancer Institute, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-4146","authenticated-orcid":false,"given":"Sylvia","family":"Fong","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"},{"name":"3Research, BioMarin Pharmaceutical, Novato, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1267-4083","authenticated-orcid":false,"given":"Matteo","family":"Franco","sequence":"additional","affiliation":[{"name":"4ProtaGene US Inc, Burlington, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choong-Ryoul","family":"Sihn","sequence":"additional","affiliation":[{"name":"3Research, BioMarin Pharmaceutical, Novato, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-8401","authenticated-orcid":false,"given":"Laura L.","family":"Swystun","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saira","family":"Afzal","sequence":"additional","affiliation":[{"name":"5ProtaGene CGT GmbH, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorianne","family":"Harpell","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hurlbut","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbey","family":"Pender","sequence":"additional","affiliation":[{"name":"1Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Su","sequence":"additional","affiliation":[{"name":"6Data Science, BioMarin Pharmaceutical, Novato, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hauke","family":"Thomsen","sequence":"additional","affiliation":[{"name":"5ProtaGene CGT GmbH, Heidelberg, Germany"},{"name":"7MSB Medical School Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Wilson","sequence":"additional","affiliation":[{"name":"6Data Science, BioMarin Pharmaceutical, Novato, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3512-8333","authenticated-orcid":false,"given":"Loubna","family":"Youssar","sequence":"additional","affiliation":[{"name":"5ProtaGene CGT GmbH, Heidelberg, 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