Chang Alex H, Sadelain Michel
Laboratory of Gene Transfer and Gene Expression, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Mol Ther. 2007 Mar;15(3):445-56. doi: 10.1038/sj.mt.6300060. Epub 2007 Jan 16.
Recent studies on the integration patterns of different categories of retroviral vectors, the genotoxicity of long-terminal repeats (LTRs) and other genetic elements, the rise of lentiviral technology and the emergence of regulated vector systems providing tissue-restricted transgene expression and RNA interference, are profoundly changing the landscape of stem cell-based therapies. New developments in vector design and an increasing understanding of the mechanisms underlying insertional oncogenesis are ushering in a new phase in hematopoietic stem cell (HSC) engineering, thus bringing the hitherto exclusive reliance on LTR-driven, gamma-retroviral vectors to an end. Based on their ability to transduce non-dividing cells and their genomic stability, lentiviral vectors offer new prospects for the manipulation of HSCs. Tissue-specific vectors, as exemplified by globin vectors, not only provide therapeutic efficacy, but may also enhance safety, insofar that they restrict transgene expression in stem cells, progenitor cells and blood cells in all but the transcriptionally targeted lineage. This review provides a survey of these advances as well as several remaining challenges, focusing in particular on the importance of achieving adequate levels of protein expression from a limited number of vector copies per cell-ideally one to two.
近期关于不同类别逆转录病毒载体整合模式、长末端重复序列（LTRs）及其他遗传元件的基因毒性、慢病毒技术的兴起以及提供组织限制性转基因表达和RNA干扰的调控载体系统的出现等研究，正在深刻改变基于干细胞的治疗格局。载体设计的新进展以及对插入性致癌作用潜在机制的深入理解，正引领造血干细胞（HSC）工程进入一个新阶段，从而终结了迄今为止对LTR驱动的γ逆转录病毒载体的完全依赖。基于其转导非分裂细胞的能力及其基因组稳定性，慢病毒载体为HSC的操控提供了新前景。以珠蛋白载体为例的组织特异性载体，不仅具有治疗效果，还可能提高安全性，因为它们可在除转录靶向谱系外的所有干细胞、祖细胞和血细胞中限制转基因表达。本综述概述了这些进展以及若干尚存的挑战，尤其关注从每个细胞有限数量的载体拷贝（理想情况下为一到两个）实现足够水平的蛋白质表达的重要性。
