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Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer

Batty, Paul; Fong, Sylvia; Franco, Matteo; Sihn, Choong-Ryoul; Swystun, Laura L; Afzal, Saira; Harpell, Lori M; ... Lillicrap, David; + view all (2024) Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer. Blood 10.1182/blood.2023022589. (In press). Green open access

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Abstract

Gene therapy using adeno-associated viral (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multi-year 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 = 4, hemizygous, and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was non-integrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency= 9.3e-4 sites/cell), with small numbers of non-random 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.

Type: Article
Title: Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2023022589
Publisher version: https://doi.org/10.1182/blood.2023022589
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: https://discovery.ucl.ac.uk/id/eprint/10189358
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