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）载体的基因治疗显示出巨大的临床前景。以前，我们表明，静脉注射rAAV可能会导致新生小鼠肝细胞癌（HCC），由于载体整合和激活染色体12上的一个特定位点，我们称之为AAV-HCC位点在这个建议。即使是单一整合事件也足以在小鼠中引起HCC。鉴于该基因座在人类HCC的一个亚类中高度保守和过表达，这些小鼠研究引起了对人类基因治疗试验中HCC诱导的可能风险的重大关注。为了推进肝脏靶向rAAV治疗的前景，重要的是要确定rAAV是否可能在人类中引起HCC。在该提案中，我们系统地探索了由AAV-HCC位点处的载体整合引起的HCC的风险，使用三种不同的动物模型来建立临床相关风险因素以及载体设计对HC诱导的影响。此外，我们将评估rAAV基因治疗载体在肝脏中随机整合所带来的风险。我们的研究结果将对肝脏定向基因治疗的临床实践产生重大影响，不仅对于rAAV载体，而且对于任何整合载体，并可能导致新的人类HCC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.