Sequence- and target-independent angiogenesis suppression by siRNA via TLR3
Identifieur interne : 001965 ( Main/Exploration ); précédent : 001964; suivant : 001966Sequence- and target-independent angiogenesis suppression by siRNA via TLR3
Auteurs : Mark E. Kleinman ; Kiyoshi Yamada ; Atsunobu Takeda ; Vasu Chandrasekaran [États-Unis] ; Miho Nozaki ; Judit Z. Baffi ; Romulo J. C. Albuquerque [États-Unis] ; Satoshi Yamasaki [Japon] ; Masahiro Itaya [Japon] ; Yuzhen Pan [États-Unis] ; Binoy Appukuttan [États-Unis] ; Daniel Gibbs [États-Unis] ; Zhenglin Yang [États-Unis] ; Katalin Karik [États-Unis] ; Balamurali K. Ambati [États-Unis] ; Traci A. Wilgus [États-Unis] ; Luisa A. Dipietro [États-Unis] ; Eiji Sakurai [Japon] ; Kang Zhang [États-Unis] ; Justine R. Smith [États-Unis] ; Ethan W. Taylor [États-Unis] ; Jayakrishna Ambati [États-Unis]Source :
- Nature [ 0028-0836 ] ; 2008-04-03.
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.
Url:
DOI: 10.1038/nature06765
Affiliations:
- Japon, États-Unis
- Caroline du Nord
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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Kleinman</name></author><author><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name></author><author><name sortKey="Takeda, Atsunobu" sort="Takeda, Atsunobu" uniqKey="Takeda A" first="Atsunobu" last="Takeda">Atsunobu Takeda</name></author><author><name sortKey="Chandrasekaran, Vasu" sort="Chandrasekaran, Vasu" uniqKey="Chandrasekaran V" first="Vasu" last="Chandrasekaran">Vasu Chandrasekaran</name></author><author><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name></author><author><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. 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Kleinman</name><affiliation></affiliation><affiliation><wicri:noCountry code="no comma">These authors contributed equally to this work.</wicri:noCountry></affiliation></author><author><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name><affiliation></affiliation><affiliation><wicri:noCountry code="no comma">These authors contributed equally to this work.</wicri:noCountry></affiliation></author><author><name sortKey="Takeda, Atsunobu" sort="Takeda, Atsunobu" uniqKey="Takeda A" first="Atsunobu" last="Takeda">Atsunobu Takeda</name><affiliation></affiliation><affiliation><wicri:noCountry code="no comma">These authors contributed equally to this work.</wicri:noCountry></affiliation></author><author><name sortKey="Chandrasekaran, Vasu" sort="Chandrasekaran, Vasu" uniqKey="Chandrasekaran V" first="Vasu" last="Chandrasekaran">Vasu Chandrasekaran</name><affiliation wicri:level="4"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290</wicri:regionArea><orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName><placeName><settlement type="city">Chapel Hill (Caroline du Nord)</settlement><region type="state">Caroline du Nord</region></placeName></affiliation></author><author><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><affiliation><wicri:noCountry code="subField"></wicri:noCountry></affiliation></author><author><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40506</wicri:regionArea><wicri:noRegion>Kentucky 40506</wicri:noRegion></affiliation></author><author><name sortKey="Yamasaki, Satoshi" sort="Yamasaki, Satoshi" uniqKey="Yamasaki S" first="Satoshi" last="Yamasaki">Satoshi Yamasaki</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601</wicri:regionArea><wicri:noRegion>Nagoya 467-8601</wicri:noRegion></affiliation></author><author><name sortKey="Itaya, Masahiro" sort="Itaya, Masahiro" uniqKey="Itaya M" first="Masahiro" last="Itaya">Masahiro Itaya</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601</wicri:regionArea><wicri:noRegion>Nagoya 467-8601</wicri:noRegion></affiliation></author><author><name sortKey="Pan, Yuzhen" sort="Pan, Yuzhen" uniqKey="Pan Y" first="Yuzhen" last="Pan">Yuzhen Pan</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239</wicri:regionArea><wicri:noRegion>Oregon 97239</wicri:noRegion></affiliation></author><author><name sortKey="Appukuttan, Binoy" sort="Appukuttan, Binoy" uniqKey="Appukuttan B" first="Binoy" last="Appukuttan">Binoy Appukuttan</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239</wicri:regionArea><wicri:noRegion>Oregon 97239</wicri:noRegion></affiliation></author><author><name sortKey="Gibbs, Daniel" sort="Gibbs, Daniel" uniqKey="Gibbs D" first="Daniel" last="Gibbs">Daniel Gibbs</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132</wicri:regionArea><wicri:noRegion>Utah 84132</wicri:noRegion></affiliation></author><author><name sortKey="Yang, Zhenglin" sort="Yang, Zhenglin" uniqKey="Yang Z" first="Zhenglin" last="Yang">Zhenglin Yang</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132</wicri:regionArea><wicri:noRegion>Utah 84132</wicri:noRegion></affiliation></author><author><name sortKey="Karik, Katalin" sort="Karik, Katalin" uniqKey="Karik K" first="Katalin" last="Karik">Katalin Karik</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104</wicri:regionArea><wicri:noRegion>Pennsylvania 19104</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah 84148</wicri:regionArea><wicri:noRegion>Utah 84148</wicri:noRegion></affiliation></author><author><name sortKey="Wilgus, Traci A" sort="Wilgus, Traci A" uniqKey="Wilgus T" first="Traci A." last="Wilgus">Traci A. Wilgus</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Wound Healing & Tissue Regeneration, University of Illinois at Chicago College of Dentistry, Chicago, Illinois 60612-7211</wicri:regionArea><wicri:noRegion>Illinois 60612-7211</wicri:noRegion></affiliation></author><author><name sortKey="Dipietro, Luisa A" sort="Dipietro, Luisa A" uniqKey="Dipietro L" first="Luisa A." last="Dipietro">Luisa A. Dipietro</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Center for Wound Healing & Tissue Regeneration, University of Illinois at Chicago College of Dentistry, Chicago, Illinois 60612-7211</wicri:regionArea><wicri:noRegion>Illinois 60612-7211</wicri:noRegion></affiliation></author><author><name sortKey="Sakurai, Eiji" sort="Sakurai, Eiji" uniqKey="Sakurai E" first="Eiji" last="Sakurai">Eiji Sakurai</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Ophthalmology, Nagoya City University Medical School, Nagoya 467-8601</wicri:regionArea><wicri:noRegion>Nagoya 467-8601</wicri:noRegion></affiliation></author><author><name sortKey="Zhang, Kang" sort="Zhang, Kang" uniqKey="Zhang K" first="Kang" last="Zhang">Kang Zhang</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Program in Human Molecular Biology and Genetics, Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84132</wicri:regionArea><wicri:noRegion>Utah 84132</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Justine R" sort="Smith, Justine R" uniqKey="Smith J" first="Justine R." last="Smith">Justine R. Smith</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97239</wicri:regionArea><wicri:noRegion>Oregon 97239</wicri:noRegion></affiliation></author><author><name sortKey="Taylor, Ethan W" sort="Taylor, Ethan W" uniqKey="Taylor E" first="Ethan W." last="Taylor">Ethan W. Taylor</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Laboratory for Molecular Medicine, University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170</wicri:regionArea><wicri:noRegion>North Carolina 27402-6170</wicri:noRegion></affiliation></author><author><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><affiliation></affiliation><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology, University of Kentucky, Lexington, Kentucky 40506</wicri:regionArea><wicri:noRegion>Kentucky 40506</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Nature</title><idno type="ISSN">0028-0836</idno><idno type="eISSN">1476-4687</idno><imprint><publisher>Nature Publishing Group</publisher><date when="2008-04-03">2008-04-03</date><biblScope unit="vol">452</biblScope><biblScope unit="issue">7187</biblScope><biblScope unit="page" from="591">591</biblScope><biblScope unit="page" to="597">597</biblScope><date type="Copyright" when="2008">2008</date></imprint><idno type="ISSN">0028-0836</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0028-0836</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">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.</div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Caroline du Nord</li></region><settlement><li>Chapel Hill (Caroline du Nord)</li></settlement><orgName><li>Université de Caroline du Nord à Chapel Hill</li></orgName></list><tree><noCountry><name sortKey="Baffi, Judit Z" sort="Baffi, Judit Z" uniqKey="Baffi J" first="Judit Z." last="Baffi">Judit Z. Baffi</name><name sortKey="Kleinman, Mark E" sort="Kleinman, Mark E" uniqKey="Kleinman M" first="Mark E." last="Kleinman">Mark E. Kleinman</name><name sortKey="Nozaki, Miho" sort="Nozaki, Miho" uniqKey="Nozaki M" first="Miho" last="Nozaki">Miho Nozaki</name><name sortKey="Takeda, Atsunobu" sort="Takeda, Atsunobu" uniqKey="Takeda A" first="Atsunobu" last="Takeda">Atsunobu Takeda</name><name sortKey="Yamada, Kiyoshi" sort="Yamada, Kiyoshi" uniqKey="Yamada K" first="Kiyoshi" last="Yamada">Kiyoshi Yamada</name></noCountry><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Chandrasekaran, Vasu" sort="Chandrasekaran, Vasu" uniqKey="Chandrasekaran V" first="Vasu" last="Chandrasekaran">Vasu Chandrasekaran</name></region><name sortKey="Albuquerque, Romulo J C" sort="Albuquerque, Romulo J C" uniqKey="Albuquerque R" first="Romulo J. C." last="Albuquerque">Romulo J. C. Albuquerque</name><name sortKey="Ambati, Balamurali K" sort="Ambati, Balamurali K" uniqKey="Ambati B" first="Balamurali K." last="Ambati">Balamurali K. Ambati</name><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><name sortKey="Ambati, Jayakrishna" sort="Ambati, Jayakrishna" uniqKey="Ambati J" first="Jayakrishna" last="Ambati">Jayakrishna Ambati</name><name sortKey="Appukuttan, Binoy" sort="Appukuttan, Binoy" uniqKey="Appukuttan B" first="Binoy" last="Appukuttan">Binoy Appukuttan</name><name sortKey="Dipietro, Luisa A" sort="Dipietro, Luisa A" uniqKey="Dipietro L" first="Luisa A." last="Dipietro">Luisa A. Dipietro</name><name sortKey="Gibbs, Daniel" sort="Gibbs, Daniel" uniqKey="Gibbs D" first="Daniel" last="Gibbs">Daniel Gibbs</name><name sortKey="Karik, Katalin" sort="Karik, Katalin" uniqKey="Karik K" first="Katalin" last="Karik">Katalin Karik</name><name sortKey="Pan, Yuzhen" sort="Pan, Yuzhen" uniqKey="Pan Y" first="Yuzhen" last="Pan">Yuzhen Pan</name><name sortKey="Smith, Justine R" sort="Smith, Justine R" uniqKey="Smith J" first="Justine R." last="Smith">Justine R. Smith</name><name sortKey="Taylor, Ethan W" sort="Taylor, Ethan W" uniqKey="Taylor E" first="Ethan W." last="Taylor">Ethan W. Taylor</name><name sortKey="Wilgus, Traci A" sort="Wilgus, Traci A" uniqKey="Wilgus T" first="Traci A." last="Wilgus">Traci A. Wilgus</name><name sortKey="Yang, Zhenglin" sort="Yang, Zhenglin" uniqKey="Yang Z" first="Zhenglin" last="Yang">Zhenglin Yang</name><name sortKey="Zhang, Kang" sort="Zhang, Kang" uniqKey="Zhang K" first="Kang" last="Zhang">Kang Zhang</name></country><country name="Japon"><noRegion><name sortKey="Yamasaki, Satoshi" sort="Yamasaki, Satoshi" uniqKey="Yamasaki S" first="Satoshi" last="Yamasaki">Satoshi Yamasaki</name></noRegion><name sortKey="Itaya, Masahiro" sort="Itaya, Masahiro" uniqKey="Itaya M" first="Masahiro" last="Itaya">Masahiro Itaya</name><name sortKey="Sakurai, Eiji" sort="Sakurai, Eiji" uniqKey="Sakurai E" first="Eiji" last="Sakurai">Eiji Sakurai</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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