Abstract Number: PB1109
Meeting: ISTH 2020 Congress
Background: Integration studies have shown that rAAV vector genomes remain mainly episomal after transduction of the target cells, with minimal integration into the host genome and with no association with oncogenicity or signs of malignant transformation.
Aims: The goal of our study was to investigate the integration profile of rAAV5 vector DNA into the host genome of livers collected from mice and Non-Human Primates (NHP) following IV administration of AAV5-hFIX.
Methods: Liver tissue samples from mice and cynomolgus macaques injected with AAV5-hFIX were collected 6 months after a single intravenous AAV administration. The profile of integration of the vector DNA into the host genome was analyzed by means of linear-amplification mediated polymerase chain reaction (LAM-PCR) and non-restrictive (nr) LAM-PCR. Episomal (concatemeric) and integrated forms of AAV5-hFIX derived vector DNA sequence were further characterized by deep-sequencing. Liver tissue samples from the same animals were also assessed by microscopic evaluations by a board-certified pathologist.
Results: The AAV vector sequences retrieved after (nr)LAM-PCR followed by high throughput sequencing were found to be present almost exclusively as non-integrated episomal forms. The low level of integrants was randomly distributed throughout the host genome. No specific clustering was seen in cynomolgus macaque genome, while some level of clustering around active genes was seen in the mouse but without signs of in vivo clone selection (an indicator of tumorigenic risk) in the animals. None of the animals showed any adverse findings during microscopic evaluation of the liver and no signs of malignant transformation were found.
Conclusions: Administration of AAV5-hFIX to mice and NHPs is associated with a low level of random integration into the livers. This integration profile does not raise any specific tumorigenic concern.
To cite this abstract in AMA style:Spronck L, de Haan M, Heijink L, Twisk J, Ferreira V, van Deventer S. Assessment of Vector Integration of AAV5-hFIX in Mice and Non-human Primates Indicates No Association with Tumorigenic Risk [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/assessment-of-vector-integration-of-aav5-hfix-in-mice-and-non-human-primates-indicates-no-association-with-tumorigenic-risk/. Accessed September 27, 2023.
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