遺傳物質(zhì)合成的小片段——小干擾RNA (small interfering RNA, siRNA) 可以阻斷異常蛋白的產(chǎn)生,，然而siRNA 候選藥物能同時誘發(fā)機(jī)體產(chǎn)生強(qiáng)烈的免疫反應(yīng),，造成毒副作用,。2009 年第2 期Oligonucleotides 上的一篇綜述文章就siRNA如何激活免疫反應(yīng),，如何檢測這些免疫反應(yīng),，以及如何設(shè)計siRNA 藥物以避免免疫反應(yīng)等siRNA 藥物開發(fā)重要研究方向,，進(jìn)行了探討,。
siRNA 是由短寡核苷酸序列組成的雙鏈結(jié)構(gòu),。自然存在和人工合成的siRNA能有效阻止疾病基因表達(dá)，這一發(fā)現(xiàn)引起了研究人員開發(fā)siRNA 藥物的濃厚興趣,。然而,，由于siRNA 的特殊結(jié)構(gòu)、序列以及藥物釋放方式,，它可能引起人體強(qiáng)烈的先天免疫反應(yīng),，刺激炎癥細(xì)胞因子和干擾素等化學(xué)物質(zhì)的釋放。
為了合成新型siRNA 并設(shè)計新的藥物釋放方式,，同時消除毒副作用,，研究人員正在努力了解siRNA 刺激免疫系統(tǒng)的機(jī)制。文章中,，來自加拿大Tekmira制藥公司的研究人員闡述了各種類型細(xì)胞中siRNA 激活免疫反應(yīng)的可能機(jī)制,，給出了化學(xué)修飾后具有最小免疫原性的siRNA 序列和結(jié)構(gòu)，并提出研究siRNA治療安全性的實驗方法,。
作者總結(jié),，通過應(yīng)用基于充分理論依據(jù)的siRNA 序列設(shè)計，并使用越來越有效的藥物輸送系統(tǒng),，siRNA 將很快用于人體受試者的系統(tǒng)性驗證分析,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
