Powers John M, Trobridge Grant D
Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington, USA.
Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington, USA ; School of Molecular Biosciences, Washington State University, Pullman, Washington, USA.
J Stem Cell Res Ther. 2013 Sep 1;2013(Suppl 3):S3:004-. doi: 10.4172/2157-7633.S3-004.
Hematopoietic stem cell (HSC) therapy using replication-incompetent retroviral vectors is a promising approach to provide life-long correction for genetic defects. HSC gene therapy clinical studies have resulted in functional cures for several diseases, but in some studies clonal expansion or leukemia has occurred. This is due to the dyregulation of endogenous host gene expression from vector provirus insertional mutagenesis. Insertional mutagenesis screens using replicating retroviruses have been used extensively to identify genes that influence oncogenesis. However, retroviral mutagenesis screens can also be used to determine the role of genes in biological processes such as stem cell engraftment. The aim of this review is to describe the potential for vector insertion site data from gene therapy studies to provide novel insights into mechanisms of HSC engraftment. In HSC gene therapy studies dysregulation of host genes by replication-incompetent vector proviruses may lead to enrichment of repopulating clones with vector integrants near genes that influence engraftment. Thus, data from HSC gene therapy studies can be used to identify novel candidate engraftment genes. As HSC gene therapy use continues to expand, the vector insertion site data collected will be of great interest to help identify novel engraftment genes and may ultimately lead to new therapies to improve engraftment.
使用无复制能力的逆转录病毒载体进行造血干细胞（HSC）治疗是一种有望为基因缺陷提供终身矫正的方法。HSC基因治疗临床研究已使多种疾病得到功能性治愈，但在一些研究中出现了克隆性扩增或白血病。这是由于载体前病毒插入诱变导致内源性宿主基因表达失调所致。使用复制型逆转录病毒进行的插入诱变筛选已被广泛用于鉴定影响肿瘤发生的基因。然而，逆转录病毒诱变筛选也可用于确定基因在诸如干细胞植入等生物学过程中的作用。本综述的目的是描述基因治疗研究中载体插入位点数据为深入了解HSC植入机制提供新见解的潜力。在HSC基因治疗研究中，无复制能力的载体前病毒导致宿主基因失调，可能会使携带影响植入的基因附近载体整合体的再增殖克隆富集。因此，HSC基因治疗研究的数据可用于鉴定新的候选植入基因。随着HSC基因治疗应用的不断扩大，所收集的载体插入位点数据将有助于鉴定新的植入基因，并最终可能带来改善植入的新疗法，从而备受关注。
