Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
Hum Gene Ther. 2013 Feb;24(2):119-31. doi: 10.1089/hum.2012.203.
Gene transfer vectors derived from oncoretroviruses or lentiviruses are the most robust and reliable tools to stably integrate therapeutic transgenes in human cells for clinical applications. Integration of these vectors in the genome may, however, have undesired effects caused by insertional deregulation of gene expression at the transcriptional or post-transcriptional level. The occurrence of severe adverse events in several clinical trials involving the transplantation of stem cells genetically corrected with retroviral vectors showed that insertional mutagenesis is not just a theoretical event, and that retroviral transgenesis is associated with a finite risk of genotoxicity. In addressing these issues, the gene therapy community offered a spectacular example of how scientific knowledge and technology can be put to work to understand the causes of unpredicted side effects, design new vectors, and develop tools and models to predict their safety and efficacy. As an added benefit, these efforts brought new basic knowledge on virus-host interactions and on the biology and dynamics of human somatic stem cells. This review summarizes the current knowledge on the interactions between retroviruses and the human genome and addresses the impact of target site selection on the safety of retroviral vector-mediated gene therapy.
来自逆转录病毒或慢病毒的基因转移载体是将治疗性转基因稳定整合到人类细胞中用于临床应用的最强大和可靠的工具。然而，这些载体在基因组中的整合可能会导致转录或转录后水平基因表达的插入调控失调而产生不良影响。在涉及用逆转录病毒载体遗传校正的干细胞移植的几项临床试验中出现严重不良事件表明，插入突变不仅是一个理论事件，而且逆转录转导与有限的遗传毒性风险相关。在解决这些问题时，基因治疗界提供了一个精彩的例子，说明如何利用科学知识和技术来了解意外副作用的原因，设计新的载体，并开发工具和模型来预测其安全性和疗效。作为一个额外的好处，这些努力带来了关于病毒-宿主相互作用以及人类体细胞干细胞的生物学和动力学的新的基础知识。本文综述了逆转录病毒与人类基因组相互作用的最新知识，并探讨了靶位点选择对逆转录病毒载体介导的基因治疗安全性的影响。
