Publication Date:
2008-03-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642938/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinman, Mark E -- Yamada, Kiyoshi -- Takeda, Atsunobu -- Chandrasekaran, Vasu -- Nozaki, Miho -- Baffi, Judit Z -- Albuquerque, Romulo J C -- Yamasaki, Satoshi -- Itaya, Masahiro -- Pan, Yuzhen -- Appukuttan, Binoy -- Gibbs, Daniel -- Yang, Zhenglin -- Kariko, Katalin -- Ambati, Balamurali K -- Wilgus, Traci A -- DiPietro, Luisa A -- Sakurai, Eiji -- Zhang, Kang -- Smith, Justine R -- Taylor, Ethan W -- Ambati, Jayakrishna -- R01 EY015422/EY/NEI NIH HHS/ -- R01 EY015422-04/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-02/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-01/EY/NEI NIH HHS/ -- England -- Nature. 2008 Apr 3;452(7187):591-7. doi: 10.1038/nature06765. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368052" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line
;
Endothelial Cells/metabolism
;
Genetic Therapy/*methods
;
Humans
;
Immunity, Innate/*immunology
;
Interferon-gamma/immunology
;
Interleukin-12/immunology
;
Macular Degeneration/complications/genetics/therapy
;
Mice
;
Mice, Inbred C57BL
;
Neovascularization, Pathologic/genetics/*immunology/*prevention & control/therapy
;
RNA, Small Interfering/chemistry/genetics/*immunology/*metabolism
;
Toll-Like Receptor 3/chemistry/genetics/*metabolism
;
Vascular Endothelial Growth Factor A/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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