[Sequence- and target-independent angiogenesis suppression by siRNA via TLR3]
>>Nature advance online publication 26 March 2008 | doi:10.1038/nature06765; Received 11 October 2007; Accepted 31 January 2008; Published online 26 March 2008
Sequence- and target-independent angiogenesis suppression by siRNA via TLR3
Mark E. Kleinman1,12, Kiyoshi Yamada1,12, Atsunobu Takeda1,12, Vasu Chandrasekaran3, Miho Nozaki1, Judit Z. Baffi1, Romulo J. C. Albuquerque1,2, Satoshi Yamasaki4, Masahiro Itaya4, Yuzhen Pan5, Binoy Appukuttan5, Daniel Gibbs6,7, Zhenglin Yang6,7, Katalin Karikó8, Balamurali K. Ambati6,9, Traci A. Wilgus10, Luisa A. DiPietro10, Eiji Sakurai4, Kang Zhang6,7, Justine R. Smith5, Ethan W. Taylor11 & Jayakrishna Ambati1,2
Departments of Ophthalmology & Visual Sciences, and,
Department of Physiology, University of Kentucky, Lexington, Kentucky 40506, USA
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA
Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601, Japan
Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239, USA
Department of Ophthalmology and Visual Sciences, Moran Eye Center,
Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148, USA
Center for Wound Healing & Tissue Regeneration, University of Illinois at Chicago College of Dentistry, Chicago, Illinois 60612-7211, USA
Laboratory for Molecular Medicine, University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170, USA
These authors contributed equally to this work.
Correspondence to: Jayakrishna Ambati1,2 Correspondence and requests for materials should be addressed to J.A. (Email: jamba2@email.uky.edu).
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-/ 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- 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.<<
Derek Lowe translates:
pipeline.corante.com
Definitely bad news for companies in the space, no matter what their targets are. Even if the off target or side effects are OK, if anyone stitching together a 21 unit siRNA can treat a disease, what are the IP and market implications?
Cheers, Tuck |
