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).
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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.
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