Sequence- and target-independent angiogenesis suppression by siRNA via TLR3

Article

关键词: TOLL-LIKE RECEPTOR-3;    DOUBLE-STRANDED-RNA;    SMALL INTERFERING RNAS;    IN-VIVO DELIVERY;    NF-KAPPA-B;    CHOROIDAL NEOVASCULARIZATION;    OCULAR NEOVASCULARIZATION;    NEGATIVE REGULATOR;    ENDOTHELIAL-CELLS;    SIGNALING PATHWAY;   

DOI  :  10.1038/nature06765

来源: SCIE

【 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). Weshow 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.

【 授权许可】

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