He Weijing, Qiang Mei, Ma Wuqiong, Valente Anthony J, Quinones Marlon P, Wang Wen, Reddick Robert L, Xiao Qifu, Ahuja Seema S, Clark Robert A, Freeman Gregory L, Li Senlin
Department of Medicine, University of Texas Health Science Center at San Antonio, and South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229-3900, USA.
Hum Gene Ther. 2006 Sep;17(9):949-59. doi: 10.1089/hum.2006.17.949.
Macrophages have the potential to deliver therapeutic genes to many target tissues. Macrophage-specific synthetic promoters (SPs) generated by random ligation of myeloid/macrophage cis elements had activity up to 100-fold that of a native macrophage promoter in macrophage cell lines, but were minimally active in nonmyeloid cells. Mouse bone marrow cells (BMCs) transduced ex vivo with lentivectors expressing green fluorescent protein (GFP) driven either by an SP (SP-GFP) or a cytomegalovirus (CMV) promoter (CMV-GFP) were used for syngeneic transplantation of lethally irradiated mice. Blood leukocytes showed stable GFP expression for up to 15 months after transplantation. SP-GFP expression was selective for CD11b+ macrophages, whereas CMV-GFP expression was observed in erythrocytes, as well as in both CD11b+ and CD11b- leukocytes. Furthermore, SP-GFP expression was much stronger than CMV-GFP expression in CD11b+ macrophages. apoE-/- BMCs transduced with the lentiviral vector encoding human apoE were used to transplant apoE-/- mice. Macrophage expression of apoE from 10 to 26 weeks of age significantly reduced atherosclerotic lesions in recipient apoE-/- mice. Thus, the novel SPs, especially when combined with lentivectors, are useful for macrophage-specific delivery of therapeutic genes.
巨噬细胞有潜力将治疗性基因传递到许多靶组织。通过髓系/巨噬细胞顺式元件随机连接产生的巨噬细胞特异性合成启动子（SPs）在巨噬细胞系中的活性比天然巨噬细胞启动子高100倍，但在非髓系细胞中的活性极低。用表达由SP（SP-GFP）或巨细胞病毒（CMV）启动子驱动的绿色荧光蛋白（GFP）的慢病毒载体体外转导小鼠骨髓细胞（BMCs），用于对致死性照射小鼠进行同基因移植。移植后长达15个月，血液白细胞显示出稳定的GFP表达。SP-GFP表达对CD11b +巨噬细胞具有选择性，而在红细胞以及CD11b +和CD11b-白细胞中均观察到CMV-GFP表达。此外，在CD11b +巨噬细胞中，SP-GFP表达比CMV-GFP表达强得多。用编码人载脂蛋白E的慢病毒载体转导的载脂蛋白E-/-BMCs用于移植载脂蛋白E-/-小鼠。10至26周龄时巨噬细胞中载脂蛋白E的表达显著减少了受体载脂蛋白E-/-小鼠的动脉粥样硬化病变。因此，新型SPs，特别是与慢病毒载体结合使用时，可用于巨噬细胞特异性递送治疗性基因。
