Liver Cancer Risk with rAAV Gene Therapy

rAAV 基因治疗的肝癌风险

基本信息

批准号：
9233058
负责人：
Markus Grompe
金额：
$ 58.59万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9233058
关键词：
Adult Alcohols Animal Model CRISPR/Cas technology Cells Chromosomes, Human, Pair 12 Chronic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Development Dose Enhancers Event Experimental Models Eye diseases Fatty acid glycerol esters Female Frequencies Future Gene Targeting Gene Transduction Agent Gene therapy trial Genome Hemophilia A Hepatocyte Hereditary Disease Human Injectable Injection of therapeutic agent Insertional Mutagenesis Intravenous Lead Liver Longitudinal Studies Macaca mulatta Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver MicroRNAs Modeling Monitor Monkeys Mus Newborn Infant Outcome Patients Primary carcinoma of the liver cells Recombinant adeno-associated virus (rAAV)Reporting Resistance Risk Risk Factors Small Nucleolar RNA System Technology Testing Transplantation Virus Diseases age effect cancer risk clinical effect clinical practice clinically relevant cohort design experimental study follow-up gene therapy homologous recombination human disease in vivo lipoprotein lipase liver cell proliferation liver injury male neonate nonhuman primate nuclease overexpression predictive modeling promoter public health relevance success tumor vector

Adult Alcohols Animal Model CRISPR/Cas technology Cells Chromosomes, Human, Pair 12 Chronic Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Data Development Dose Enhancers Event Experimental Models Eye diseases Fatty acid glycerol esters Female Frequencies Future Gene Targeting Gene Transduction Agent Gene therapy trial Genome Hemophilia A Hepatocyte Hereditary Disease Human Injectable Injection of therapeutic agent Insertional Mutagenesis Intravenous Lead Liver Longitudinal Studies Macaca mulatta Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver MicroRNAs Modeling Monitor Monkeys Mus Newborn Infant Outcome Patients Primary carcinoma of the liver cells Recombinant adeno-associated virus (rAAV)Reporting Resistance Risk Risk Factors Small Nucleolar RNA System Technology Testing Transplantation Virus Diseases age effect cancer risk clinical effect clinical practice clinically relevant cohort design experimental study follow-up gene therapy homologous recombination human disease in vivo lipoprotein lipase liver cell proliferation liver injury male neonate nonhuman primate nuclease overexpression predictive modeling promoter public health relevance success tumor vector

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项目摘要

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.

描述（由申请人提供）：基于重组腺相关病毒（RAAV）载体的基因治疗表现出巨大的临床希望。以前，我们表明，静脉注射RAAV注射可能会导致新生小鼠的肝细胞癌（HCC），这是由于载体整合到12号染色体上的特定基因座的载体整合并激活，我们在此提案中称其为AAV-HCC基因座。即使是单个集成事件也足以引起小鼠的HCC。鉴于该基因座在人类HCC的子类中高度保守和过表达，因此这些小鼠研究对人类基因治疗试验中可能存在HCC的风险引起了重大关注。为了促进现场指导的RAAV疗法的承诺领域，重要的是确定Raav是否可能在人类中引起HCC。在此提案中，我们使用三种不同的动物模型来系统地探索由AAV-HCC基因座的向量积分引起的HCC风险，以建立临床相关的危险因素的影响以及矢量设计对HC诱导的影响。此外，我们将评估肝脏中RAAV基因疗法向量随机整合所带来的风险。我们的结果将对肝脏定向的基因疗法的临床实践产生重大影响，不仅对RAAV矢量，而且对任何整合载体，并且可能导致人类HCC的新实验模型。