Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Sydney, New South Wales, Australia.
Bioinformatics Unit, Children's Medical Research Institute, University of Sydney, Sydney, New South Wales, Australia.
Nat Genet. 2017 Aug;49(8):1267-1273. doi: 10.1038/ng.3893. Epub 2017 Jun 19.
Vectors based on adeno-associated virus type 2 (AAV2) are powerful tools for gene transfer and genome editing applications. The level of interest in this system has recently surged in response to reports of therapeutic efficacy in human clinical trials, most notably for those in patients with hemophilia B (ref. 3). Understandably, a recent report drawing an association between AAV2 integration events and human hepatocellular carcinoma (HCC) has generated controversy about the causal or incidental nature of this association and the implications for AAV vector safety. Here we describe and functionally characterize a previously unknown liver-specific enhancer-promoter element in the wild-type AAV2 genome that is found between the stop codon of the cap gene, which encodes proteins that form the capsid, and the right-hand inverted terminal repeat. This 124-nt sequence is within the 163-nt common insertion region of the AAV genome, which has been implicated in the dysregulation of known HCC driver genes and thus offers added insight into the possible link between AAV integration events and the multifactorial pathogenesis of HCC.
基于腺相关病毒 2 型 (AAV2) 的载体是基因转移和基因组编辑应用的强大工具。最近，由于人类临床试验中治疗效果的报告，人们对该系统的兴趣大增，尤其是对乙型血友病患者的治疗效果（参考文献 3）。可以理解的是，最近的一份报告将 AAV2 整合事件与人类肝细胞癌 (HCC) 联系起来，这引发了关于这种关联的因果关系或偶然性质以及对 AAV 载体安全性的影响的争议。在这里，我们描述并功能表征了野生型 AAV2 基因组中一个以前未知的肝脏特异性增强子-启动子元件，该元件位于编码衣壳蛋白的 cap 基因的终止密码子和右手反向末端重复之间。该 124nt 序列位于 AAV 基因组的 163nt 常见插入区，该插入区与已知 HCC 驱动基因的失调有关，因此为 AAV 整合事件与 HCC 的多因素发病机制之间的可能联系提供了更多的见解。
