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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, Lorianne ; Hurlbut, David ; Pender, Abbey and Su, Cheng , et al. (2024) In Blood 143(23). p.2373-2385
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... (More)
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. (Less)
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publishing date
type
Contribution to journal
publication status
published
in
Blood
volume
143
issue
23
pages
2373 - 2385
publisher
American Society of Hematology
external identifiers
  • pmid:38452208
  • scopus:85190807806
ISSN
1528-0020
DOI
10.1182/blood.2023022589
language
English
LU publication?
no
id
ab35a0b2-db7a-43ec-bf61-f8913f1f4395
date added to LUP
2024-03-15 12:19:08
date last changed
2024-10-14 12:00:57
@article{ab35a0b2-db7a-43ec-bf61-f8913f1f4395,
  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.}},
  author       = {{Batty, Paul and Fong, Sylvia and Franco, Matteo and Sihn, Choong-Ryoul and Swystun, Laura L. and Afzal, Saira and Harpell, Lorianne and Hurlbut, David and Pender, Abbey and Su, Cheng and Thomsen, Hauke and Wilson, Christopher and Youssar, Loubna and Winterborn, Andrew and Gil-Farina, Irene and Lillicrap, David}},
  issn         = {{1528-0020}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{23}},
  pages        = {{2373--2385}},
  publisher    = {{American Society of Hematology}},
  series       = {{Blood}},
  title        = {{Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer}},
  url          = {{http://dx.doi.org/10.1182/blood.2023022589}},
  doi          = {{10.1182/blood.2023022589}},
  volume       = {{143}},
  year         = {{2024}},
}