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

Mark E. Kleinman, Kiyoshi Yamada, Atsunobu Takeda, Vasu Chandrasekaran, Miho Nozaki, Judit Z. Baffi, Romulo J. C. Albuquerque, Satoshi Yamasaki, Masahiro 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 W. Taylor and Jayakrishna Ambati ()
Additional contact information
Mark E. Kleinman: and
Kiyoshi Yamada: and
Atsunobu Takeda: and
Vasu Chandrasekaran: The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA
Miho Nozaki: and
Judit Z. Baffi: and
Romulo J. C. Albuquerque: and
Satoshi Yamasaki: Nagoya City University Medical School
Masahiro Itaya: Nagoya City University Medical School
Yuzhen Pan: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
Binoy Appukuttan: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
Daniel Gibbs: Moran Eye Center
Zhenglin Yang: Moran Eye Center
Katalin Karikó: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Balamurali K. Ambati: Moran Eye Center
Traci A. Wilgus: Center for Wound Healing & Tissue Regeneration, University of Illinois at Chicago College of Dentistry, Chicago, Illinois 60612-7211, USA
Luisa A. DiPietro: Center for Wound Healing & Tissue Regeneration, University of Illinois at Chicago College of Dentistry, Chicago, Illinois 60612-7211, USA
Eiji Sakurai: Nagoya City University Medical School
Kang Zhang: Moran Eye Center
Justine R. Smith: Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
Ethan W. Taylor: Laboratory for Molecular Medicine, University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170, USA
Jayakrishna Ambati: and

Nature, 2008, vol. 452, issue 7187, 591-597

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature06765

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