An Dong Sung, Donahue Robert E, Kamata Masakazu, Poon Betty, Metzger Mark, Mao Si-Hua, Bonifacino Aylin, Krouse Allen E, Darlix Jean-Luc, Baltimore David, Qin F Xiao-Feng, Chen Irvin S Y
Department of Hematology and Oncology, AIDS Institute, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13110-5. doi: 10.1073/pnas.0705474104. Epub 2007 Aug 1.
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.
RNA干扰是一种抑制基因表达的强大方法，在治疗应用方面具有巨大潜力。然而，由于内源性RNA干扰在正常细胞功能中发挥作用，因此小干扰RNA（siRNA）的递送和表达必须与安全性相平衡。在此，我们报告了通过CD34+造血干/祖细胞移植成功在灵长类动物中稳定表达靶向趋化因子（C-C基序）受体5（CCR5）的siRNA。造血重建后，至移植后14个月，我们观察到表达siRNA的淋巴细胞标记稳定，趋化因子（C-C基序）受体5表达持续下调。标记的细胞在体外对猿猴免疫缺陷病毒感染的敏感性较低。这些研究成功证明，siRNA可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，并有可能治疗诸如HIV-1等血液疾病。
