Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates
Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates
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DOI：
10.1073/pnas.0705474104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Chen, Irvin S. Y.
中科院分区：
文献类型：
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作者：
An, Dong Sung;Donahue, Robert E.;Chen, Irvin S. Y.
RNAi是一种强大的抑制基因表达的方法，具有巨大的治疗应用潜力。然而，由于内源性RNAi在正常的细胞功能中发挥作用，siRNAs的传递和表达必须与安全性相平衡。在这里，我们报道了针对趋化因子(c-c基序)受体5(CCR5)的siRNAs在灵长类动物中的稳定表达，该siRNAs通过CD34+造血干/祖细胞移植引入。造血重建后，到移植后14个月，我们观察到稳定标记的淋巴细胞表达siRNAs，趋化因子(c-c基序)受体5的表达持续下调。标记的细胞在体外不太容易受到猴免疫缺陷病毒的感染。这些研究成功地证明了siRNAs可以与造血干细胞移植一起用于稳定调节灵长类动物的基因表达，并有可能治疗HIV-1等血液疾病。
RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.