HIV vector-mediated targeted suicide gene therapy for adult T-cell leukemia
HIV vector-mediated targeted suicide gene therapy for adult T-cell leukemia
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DOI：
10.1038/sj.gt.3303024
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发表时间：
2007-12
期刊：
影响因子：
5.1
通讯作者：
K. Miyake;K. Inokuchi;N. Miyake;K. Dan;T. Shimada
中科院分区：
文献类型：
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作者：
K. Miyake;K. Inokuchi;N. Miyake;K. Dan;T. Shimada
我们研究了使用单纯疱疹病毒胸苷激酶（HSV-TK）介导的自杀系统的基因治疗方法治疗成人T细胞白血病（ATL）的潜在疗效。构建了含有HSV-TK基因的基于人类免疫缺陷病毒（HIV）的载体，以实现靶向基因转移到CD 4阳性ATL细胞中，之后转导的细胞通过更昔洛韦（GCV）处理被选择性地杀死。为了检查HIV载体在体内的效用，通过将1× 10 7个MT 2细胞腹腔注射到NK耗尽的非肥胖型糖尿病/严重免疫缺陷（NOD-SCID）小鼠中来制备ATL-NOD-SCID小鼠。此后，将1 ml浓缩的表达HSV-TK（HXCTKN）或GFP（HXGFP）的HIV载体原液注射到腹腔内，并每天两次给予GCV，持续5天。荧光激活细胞分选（FACS）分析显示7-11%的从腹膜腔回收的MT 2或HUT 102细胞用HXGFP转导。3周后，HXCTKN组小鼠血浆sIL 2-Rα水平显著低于HXGFP组。此外，注射HXCTKN的小鼠存活时间明显长于注射HXGFP的小鼠。总之，这些发现表明，HIV载体可用于体内靶向基因转移到ATL细胞中，因此可作为开发治疗ATL的有效新疗法的基础。
We investigated the potential efficacy of treating adult T-cell leukemia (ATL) using a gene therapeutic approach involving the use of a herpes simplex virus–thymidine kinase (HSV-TK)-mediated suicide system. Human immunodeficiency virus (HIV)-based vectors containing the HSV-TK gene were constructed to achieve targeted gene transfer into CD4-positive ATL cells, after which the transduced cells were selectively killed by treatment with ganciclovir (GCV). To examine the utility of HIV vectors in vivo, ATL-NOD-SCID mice were prepared by intraperitoneal injection of 1× 10 7 MT2 cells into NK-depleted nonobese diabetic/severely compromised immunodeficient (NOD-SCID) mice. Thereafter, 1 ml of concentrated HIV vector expressing HSV-TK (HXCTKN) or GFP (HXGFP) stock was injected into the intraperitoneal cavity, and GCV was administered twice a day for 5 days. Fluorescence-activated cell sorting (FACS) analysis showed that 7–11% of MT2 or HUT102 cells recovered from the peritoneal cavity were transduced with the HXGFP. After 3 weeks, plasma sIL2-Rα levels were significantly lower in mice administered HXCTKN than in those administered HXGFP. Moreover, HXCTKN-injected mice survived significantly longer than HXGFP-injected mice. Taken together, these findings suggest that HIV vectors could be used for in vivo targeted gene transfer into ATL cells and could thus serve as the basis for the development of effective new therapies for the treatment of ATL.