Chu P, Lutzko C, Stewart A K, Dubé I D
Department of Laboratory Medicine, Sunnybrook Health Science Centre, University of Toronto, Ontario, Canada.
J Mol Med (Berl). 1998 Mar;76(3-4):184-92. doi: 10.1007/s001090050207.
Human hematopoietic stem cells genetically modified by retroviral-mediated gene transfer may offer new treatment options for patients with genetic disease. The potential of gene-modified hematopoietic stem cells as vehicles for gene delivery was first illustrated by the demonstration that hematopoietic systems of lethally irradiated mice can be reconstituted with retroviral vector transduced syngeneic bone marrow, and that these cells can in turn provide genetically marked progeny which persist in blood and marrow over extended time periods. In contrast, hematopoietic stem cells from large animals prove difficult to transduce with retroviral vectors and are consequently less likely to function as vehicles for long-term gene therapy. Indeed, clinically relevant levels of gene transfer into large animal and human hematopoietic stem cells has not been widely achieved. The need for improved retroviral vector systems and for understanding the biology of hematopoietic stem cell gene transfer continue to fuel intense research activity. Preliminary results from human stem cell gene marking and gene therapy trials currently underway are encouraging. This contribution reviews the underlying concepts relevant to retroviral-mediated gene transfer into hematopoietic stem cells. We survey the evolution of approaches for gene transfer into hematopoietic stem cells, from murine and large animal models to the first human clinical trials. Finally, we discuss new strategies which are currently being pursued.
通过逆转录病毒介导的基因转移进行基因改造的人类造血干细胞可能为患有遗传疾病的患者提供新的治疗选择。基因改造的造血干细胞作为基因传递载体的潜力首先通过以下证明得以体现：经逆转录病毒载体转导的同基因骨髓可以重建受致死剂量照射小鼠的造血系统，并且这些细胞反过来可以提供在血液和骨髓中长时间持续存在的基因标记后代。相比之下，大型动物的造血干细胞很难用逆转录病毒载体进行转导，因此不太可能作为长期基因治疗的载体发挥作用。事实上，尚未广泛实现将临床相关水平的基因转移到大型动物和人类造血干细胞中。对改进逆转录病毒载体系统以及理解造血干细胞基因转移生物学的需求继续推动着激烈的研究活动。目前正在进行的人类干细胞基因标记和基因治疗试验的初步结果令人鼓舞。本论文综述了与逆转录病毒介导的造血干细胞基因转移相关的基本概念。我们调查了从小鼠和大型动物模型到首次人体临床试验，向造血干细胞进行基因转移方法的演变。最后，我们讨论了目前正在探索的新策略。
