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

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Abstract Text:

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 ,Balamurali K Ambati,Traci A Wilgus,Luisa A DiPietro,Eiji Sakurai,Kang Zhang,Justine R Smith,Ethan W Taylor,Jayakrishna Ambati,

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-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.

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Publishing Authors By Initials

ME Kleinman,K Yamada,A Takeda,V Chandrasekaran,M Nozaki,JZ Baffi,RJ Albuquerque,S Yamasaki,M Itaya,Y Pan,B Appukuttan,D Gibbs,Z Yang,K ,BK Ambati,TA Wilgus,LA DiPietro,E Sakurai,K Zhang,JR Smith,EW Taylor,J Ambati,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Nature

VOLUME: 452

Page Numbers: 591-7

Journal Abbreviation:

ISSN: 1476-4687

DAY: 26

MONTH: 03

YEAR: 2008

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

Number of References:

LANGUAGE: eng

NlmUniqueID: 410462

Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.

AFFILIATION: Department of Ophthalmology, University of Kentucky, Lexington, Kentucky 40506, USA.

Country: England

AGENCY:

GRANT:

ACRONYM:

MEDLINETA: Nature

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

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

• Fifty years later: the disk goes to the prom.
• Nanoparticles sustain expression of Flt intraceptors in the cornea and inhibit injury-induced corneal angiogenesis.
• Sequence- and target-independent angiogenesis suppression by siRNA via TLR3.
• Toward a higher fidelity model of AMD.