| First Author | Chandler RJ | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 2 | Pages | 870-80 |
| PubMed ID | 25607839 | Mgi Jnum | J:220387 |
| Mgi Id | MGI:5634604 | Doi | 10.1172/JCI79213 |
| Citation | Chandler RJ, et al. (2015) Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest 125(2):870-80 |
| abstractText | 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 (Rian) locus, and the resulting overexpression of proximal microRNAs and retrotransposon-like 1 (Rtl1) were associated with HCC. In addition, we demonstrated that the AAV vector dose, enhancer/promoter selection, and the timing of gene delivery are all critical factors for determining HCC incidence after AAV gene delivery. Together, our results define aspects of AAV-mediated gene therapy that influence genotoxicity and suggest that these features should be considered for design of both safer AAV vectors and gene therapy studies. |
