遗传物质合成的小片段——小干扰RNA (small interfering RNA, siRNA) 可以阻断异常蛋白的产生,然而siRNA 候选药物能同时诱发机体产生强烈的免疫反应,造成毒副作用。2009 年第2 期Oligonucleotides 上的一篇综述文章就siRNA如何激活免疫反应,如何检测这些免疫反应,以及如何设计siRNA 药物以避免免疫反应等siRNA 药物开发重要研究方向,进行了探讨。
siRNA 是由短寡核苷酸序列组成的双链结构。自然存在和人工合成的siRNA能有效阻止疾病基因表达,这一发现引起了研究人员开发siRNA 药物的浓厚兴趣。然而,由于siRNA 的特殊结构、序列以及药物释放方式,它可能引起人体强烈的先天免疫反应,刺激炎症细胞因子和干扰素等化学物质的释放。
为了合成新型siRNA 并设计新的药物释放方式,同时消除毒副作用,研究人员正在努力了解siRNA 刺激免疫系统的机制。文章中,来自加拿大Tekmira制药公司的研究人员阐述了各种类型细胞中siRNA 激活免疫反应的可能机制,给出了化学修饰后具有最小免疫原性的siRNA 序列和结构,并提出研究siRNA治疗安全性的实验方法。
作者总结,通过应用基于充分理论依据的siRNA 序列设计,并使用越来越有效的药物输送系统,siRNA 将很快用于人体受试者的系统性验证分析。(生物谷Bioon.com)
生物谷推荐原始出处:
OLIGONUCLEOTIDES Number 2, 2009 DOI: 10.1089/oli.2009.0180
siRNA and Innate Immunity
Marjorie Robbins, Adam Judge, and Ian MacLachlan
Canonical small interfering RNA (siRNA) duplexes are potent activators of the mammalian innate immune system. The induction of innate immunity by siRNA is dependent on siRNA structure and sequence, method of delivery, and cell type. Synthetic siRNA in delivery vehicles that facilitate cellular uptake can induce high levels of infl ammatory cytokines and interferons after systemic administration in mammals and in primary human blood cell cultures. This activation is predominantly mediated by immune cells, normally via a Toll-like receptor(TLR) pathway. The siRNA sequence dependency of these pathways varies with the type and location of the TLR involved. Alternatively nonimmune cell activation may also occur, typically resulting from siRNA interaction with cytoplasmic RNA sensors such as RIG1. As immune activation by siRNA-based drugs represents an undesirable side effect due to the considerable toxicities associated with excessive cytokine release in humans,understanding and abrogating this activity will be a critical component in the development of safe and effective therapeutics. This review describes the intracellular mechanisms of innate immune activation by siRNA, the design of appropriate sequences and chemical modifi cation approaches, and suitable experimental methods for studying their effects, with a view toward reducing siRNA-mediated off-target effects.