Grünweller A, Hartmann R K
Institute for Pharmaceutical Chemistry, Philipps-Universität Marburg, Germany.
Curr Med Chem. 2005;12(26):3143-61. doi: 10.2174/092986705774933489.
The discovery of RNA interference (RNAi) in eukaryotic cells has been the major recent breakthrough in molecular and cell biology. RNAi machineries exert biological functions in gene regulation, genome defense and chromatin architecture and dynamics. The potential of RNAi to silence any gene of interest in a highly specific and efficient manner via double-stranded RNA (dsRNA) has literally revolutionized modern genetics. RNAi-based functional genomics now permits, for the first time, to evaluate the cellular role of individual gene products on a genome-wide scale in higher organisms like mammals, presenting an alternative to the generation of animal knockouts often doomed to failure because of a lethal phenotype. RNAi has had an enormous impact on the development of novel disease models in animals, and it is likely that small interfering RNAs (siRNAs), which are the trigger molecules for RNA silencing, will become an invaluable tool for the treatment of genetic diseases. First clinical trials, using siRNAs directed against the vascular endothelial growth factor (VEGF) or one of its receptors, have been initiated recently for the treatment of age-related macular degeneration. Improving guidelines for the rational design of siRNAs, based on recent progress in understanding the mechanisms underlying RNAi, as well as the introduction of chemical modifications into siRNAs are expected to improve their pharmacokinetic and pharmacodynamic properties for in vivo applications. Finally, successful therapeutic application of RNAi will depend on the development of improved siRNA delivery strategies that combine high specificity and efficiency with a low immunostimulatory and tumorigenic potential.
真核细胞中RNA干扰（RNAi）的发现是分子和细胞生物学领域近期的重大突破。RNAi机制在基因调控、基因组防御以及染色质结构与动态变化中发挥生物学功能。RNAi通过双链RNA（dsRNA）以高度特异性和高效性沉默任何感兴趣基因的潜力彻底改变了现代遗传学。基于RNAi的功能基因组学首次使得在哺乳动物等高等生物中在全基因组范围内评估单个基因产物的细胞作用成为可能，为常常因致死表型而注定失败的动物基因敲除技术提供了一种替代方法。RNAi对动物新型疾病模型的开发产生了巨大影响，并且作为RNA沉默触发分子的小干扰RNA（siRNA）很可能会成为治疗遗传疾病的宝贵工具。最近已经启动了针对血管内皮生长因子（VEGF）或其受体之一的siRNA的首次临床试验，用于治疗年龄相关性黄斑变性。基于对RNAi潜在机制理解的最新进展改进siRNA合理设计的指导原则，以及在siRNA中引入化学修饰有望改善其体内应用的药代动力学和药效学特性。最后，RNAi的成功治疗应用将取决于开发出改进的siRNA递送策略，该策略要将高特异性和高效性与低免疫刺激和致瘤潜力相结合。
