College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
J Control Release. 2010 Apr 2;143(1):88-94. doi: 10.1016/j.jconrel.2009.12.005. Epub 2010 Jan 18.
A membrane receptor, Fas (CD95), and its ligand FasL have been considered as key players in diabetes pathogenesis. They are known to mediate interactions between beta cells and cytotoxic T cells, which results in apoptotic cell death. We hypothesized that the interruption of Fas-FasL interactions by suppressing Fas expression in beta cells would affect the development of diabetes. The effect of Fas-silencing siRNA (Fas siRNA) on diabetes development was evaluated in a cyclophosphamide (CY)-accelerated diabetes animal model after intravenous administration using a polymeric carrier, polyethylenimine (PEI). The systemic non-viral delivery of Fas siRNA showed significant delay in diabetes incidence up to 40 days, while the control mice treated with naked Fas siRNA, scrambled dsRNA, or PBS were afflicted with diabetes within 20 days. The retardation of diabetes incidence after the treatment of Fas siRNA may be due to the delayed progression of the pancreatic insulitis. In this study, the potential use of a non-viral carrier based siRNA gene therapy for the prevention of type-1 diabetes is demonstrated.
一种膜受体 Fas（CD95）及其配体 FasL 被认为是糖尿病发病机制中的关键因素。它们介导β细胞与细胞毒性 T 细胞之间的相互作用，导致细胞凋亡。我们假设通过抑制β细胞中 Fas 的表达来阻断 Fas-FasL 相互作用会影响糖尿病的发展。我们使用聚合物载体聚乙烯亚胺（PEI）静脉给药，在环磷酰胺（CY）加速的糖尿病动物模型中评估了 Fas-siRNA（Fas siRNA）对糖尿病发展的影响。系统的非病毒递送 Fas siRNA 可显著延迟糖尿病的发病时间长达 40 天，而用裸 Fas siRNA、乱序 dsRNA 或 PBS 治疗的对照小鼠在 20 天内就患有糖尿病。Fas siRNA 治疗后糖尿病发病的延迟可能是由于胰岛炎的进展延迟。在这项研究中，展示了基于非病毒载体的 siRNA 基因治疗在预防 1 型糖尿病中的潜在用途。
