小干扰RNA
RNA干扰
基因沉默
生物
癌症研究
细胞生物学
血管生成
干扰素
TLR3型
先天免疫系统
核糖核酸
分子生物学
免疫学
Toll样受体
基因
遗传学
免疫系统
作者
Mark E. Kleinman,Kiyoshi Yamada,Atsunobu Takeda,V. Chandrasekaran,Miho Nozaki,Judit Baffi,Romulo Albuquerque,Satoshi Yamasaki,M. Itaya,Yuzhen Pan,Binoy Appukuttan,Daniel Gibbs,Zhenglin Yang,Katalin Karikó,Balamurali K. Ambati,Traci A. Wilgus,Luisa A. DiPietro,Eiji Sakurai,Kang Zhang,Justine R. Smith,Ethan Will Taylor,Jayakrishna Ambati
出处
期刊:Nature
[Springer Nature]
日期:2008-03-26
卷期号:452 (7187): 591-597
被引量:861
摘要
Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.
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