Liver Cancer Risk with rAAV Gene Therapy

 描述(由申请人提供)： 基于重组腺相关病毒(RAAV)载体的基因治疗正显示出巨大的临床应用前景。以前，我们发现静脉注射rAAV可以导致新生小鼠肝细胞癌，这是因为载体整合到并激活了12号染色体上的一个特定的基因座，在本方案中我们称之为AAV-HCC基因座。即使是一个单一的整合事件也足以引起小鼠的肝细胞癌。鉴于该基因在人类肝细胞癌的亚类中高度保守和过度表达，这些小鼠研究引起了人们对人类基因治疗试验中可能诱发肝细胞癌的风险的重大担忧。为了推进肝脏导向rAAV治疗的前景，很重要的一点是要确定rAAV是否可能导致人类肝细胞癌。在这个方案中，我们系统地探讨了AAV-HCC基因座上载体整合引起的肝癌的风险，使用三种不同的动物模型来建立临床相关的危险因素的影响，以及载体设计对HC诱导的影响。此外，我们将评估随机整合rAAV基因治疗载体在肝脏中所带来的风险。我们的结果将对肝脏导向基因治疗的临床实践产生重大影响，不仅对rAAV载体，而且对任何整合载体，并可能导致新的人肝细胞癌的实验模型。

 DESCRIPTION (provided by applicant): Gene therapy based on recombinant adeno-associated virus (rAAV) vectors is showing great clinical promise. Previously, we showed that an intravenous rAAV injection could cause hepatocellular carcinoma (HCC) in newborn mice due to vector integration into and activation of a specific locus on chromosome 12 which we call the AAV-HCC locus in this proposal. Even a single integration event was sufficient to cause HCC in mice. Given that this locus is highly conserved and overexpressed in a subclass of human HCC, these mouse studies raise significant concerns about a possible risk of HCC induction in human gene therapy trials. In order to advance the promising field of liver-directed rAAV therapy, it is important to establish whether rAAV is likely to cause HCC in humans. In this proposal we systematically explore the risk of HCC caused by vector integration at the AAV-HCC locus, using three different animal models to establish the effects of clinically relevant risk factors, as well as vector design on HC induction. In addition, we will assess the risk conferred by random integration of rAAV gene therapy vectors in the liver. Our results will have a significant impact on the clinical practice o liver-directed gene therapy, not only for rAAV vectors, but also for any integrating vector, and may lead to new experimental models of human HCC.