Liver Injury Increases the Incidence of HCC following AAV Gene Therapy in Mice

• Published in: Molecular therapy Vol. 29; no. 2; pp. 680 - 690
• Main Authors: Dalwadi, Dhwanil A., Torrens, Laura, Abril-Fornaguera, Jordi, Pinyol, Roser, Willoughby, Catherine, Posey, Jeffrey, Llovet, Josep M., Lanciault, Christian, Russell, David W., Grompe, Markus, Naugler, Willscott E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.02.2021; American Society of Gene & Cell Therapy
• Subjects: Animals; Carcinoma, Hepatocellular - diagnosis; Carcinoma, Hepatocellular - etiology; Dependovirus - genetics; Disease Models, Animal; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic Vectors - genetics; Incidence; Liver Diseases - complications; Liver Diseases - etiology; Liver Diseases - pathology; Liver Neoplasms - diagnosis; Liver Neoplasms - etiology; Mice; Original
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2020.10.018

Adeno-associated virus (AAV) integrates into host genomes at low frequency, but when integration occurs in oncogenic hotspots it can cause hepatocellular carcinoma (HCC). Given the possibility of recombinant AAV (rAAV) integration leading to HCC, common causes of liver inflammation like non-alcoholic fatty liver disease (NAFLD) may increase the risk of rAAV-induced HCC. A rAAV targeting the oncogenic mouse Rian locus was used, and as expected led to HCC in all mice infected as neonates, likely due to growth-related hepatocyte proliferation in young mice. Mice infected with rAAV as adults did not develop HCC unless they were fed a diet leading to NAFLD, with increased inflammation and hepatocyte proliferation. Female mice were less susceptible to rAAV-induced HCC, and male mice with NAFLD treated with estrogen exhibited less inflammation and immune exhaustion associated with oncogenesis compared to those without estrogen. Adult NAFLD mice infected with a non-targeted control rAAV also developed HCC, though only half as frequently as those exposed to the Rian targeted rAAV. This study shows that adult mice exposed to rAAV gene therapy in the context of chronic liver disease developed HCC at high frequency, and thus warrants further study in humans given the high prevalence of NAFLD in the population. [Display omitted] This study demonstrates that adult mice exposed to rAAV gene therapy in the context of chronic liver disease developed HCC at high frequency. Further, female mice are less susceptible to rAAV-induced HCC compared to males, part of which is due to a more favorable immune milieu related to estrogen.