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- Title
Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.
- Authors
Kleinman, Mark E.; Yamada, Kiyoshi; Takeda, Atsunobu; Chandrasekaran, Vasu; Nozaki, Miho; Baffi, Judit Z.; Albuquerque, Romulo J. C.; Yamasaki, Satoshi; Itaya, Masahiro; Yuzhen Pan; Appukuttan, Binoy; Gibbs, Daniel; Zhenglin Yang; Karikó, Katalin; Ambati, Balamurali K.; Wilgus, Traci A.; DiPietro, Luisa A.; Sakurai, Eiji; Kang Zhang; Smith, Justine R.
- Abstract
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-α/β 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-γ 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.
- Subjects
SMALL interfering RNA; CLINICAL trials; NEOVASCULARIZATION; VASCULAR endothelial growth factors; GENE silencing; INTERFERONS; NUCLEOTIDES; PHARMACOGENOMICS; GENE expression
- Publication
Nature, 2008, Vol 452, Issue 7187, p591
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature06765