Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog

Adeno-associated viral (AAV) vectors have traditionally been viewed as predominantly nonintegrating, with limited concerns for oncogenesis. However, accumulating preclinical data have shown that AAV vectors integrate more often than previously appreciated, with the potential for genotoxicity. To und...

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Vydané v:Molecular therapy. Methods & clinical development Ročník 31; s. 101159
Hlavní autori: Van Gorder, Lucas, Doshi, Bhavya S., Willis, Elinor, Nichols, Timothy C., Cook, Emma, Everett, John K., Merricks, Elizabeth P., Arruda, Valder R., Bushman, Frederic D., Callan, Mary Beth, Samelson-Jones, Benjamin J.
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: United States Elsevier Inc 14.12.2023
American Society of Gene & Cell Therapy
Elsevier
Predmet:
AAV
cancer
dog model
gene therapy
genotoxicity
integration
lymphoma
Original
genotoxicity
AAV
lymphoma
integration
gene therapy
cancer
dog model
ISSN:2329-0501, 2329-0501
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Shrnutí:Adeno-associated viral (AAV) vectors have traditionally been viewed as predominantly nonintegrating, with limited concerns for oncogenesis. However, accumulating preclinical data have shown that AAV vectors integrate more often than previously appreciated, with the potential for genotoxicity. To understand the consequences of AAV vector integration, vigilance for rare genotoxic events after vector administration is essential. Here, we investigate the development of multicentric lymphoma in a privately owned dog, PC9, with severe hemophilia A that was treated with an AAV8 vector encapsidating a B domain–deleted canine coagulation F8 gene. PC9 developed an aggressive B cell lineage multicentric lymphoma 3.5 years after AAV treatment. Postmortem analysis of the liver, spleen, and lymph nodes showed the expected biodistribution of the AAV genome. Integration events were found both in PC9 and a second privately owned hemophilia A dog treated similarly with canine F8 gene transfer, which died of a bleeding event without evidence of malignancy. However, we found no evidence of expanded clones harboring a single integration event, indicating that AAV genome integrations were unlikely to have contributed to PC9’s cancer. These findings suggest AAV integrations occur but are mostly not genotoxic and support the safety profile of AAV gene therapy. [Display omitted] Samelson-Jones and colleagues found no evidence to suggest that adeno-associated viral (AAV) vector integrations contributed to the development of a fatal lymphoma 3.5 years after AAV treatment in a dog with hemophilia A. Although AAV vector integrations were identified, they did not appear to be genotoxic.
Bibliografia:ObjectType-Article-1
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content type line 23
ISSN:2329-0501
2329-0501
DOI:10.1016/j.omtm.2023.101159