The use of adeno-associated virus (AAV) as a gene therapy vector has been approved recently for clinical use and has demonstrated efficacy in a growing number of clinical trials. However, the safety of AAV as a vector has been challenged by a single study that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. Most studies have not noted genotoxicity following AAV-mediated gene delivery; therefore, the possibility that there is an association between AAV and HCC is controversial. Here, we performed a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the RNA imprinted and accumulated in nucleus (
Randy J. Chandler, Matthew C. LaFave, Gaurav K. Varshney, Niraj S. Trivedi, Nuria Carrillo-Carrasco, Julien S. Senac, Weiwei Wu, Victoria Hoffmann, Abdel G. Elkahloun, Shawn M. Burgess, Charles P. Venditti
Incidence of HCC in mice followed for 18 to 22 months after intrahepatic neonatal injection of AAV vectors.