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  • 1
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    Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 (2008)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 2
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    CCR3 is a target for age-related macular degeneration diagnosis and therapy (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-06-16
    Description: Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712122/" 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/PMC2712122/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takeda, Atsunobu -- Baffi, Judit Z -- Kleinman, Mark E -- Cho, Won Gil -- Nozaki, Miho -- Yamada, Kiyoshi -- Kaneko, Hiroki -- Albuquerque, Romulo J C -- Dridi, Sami -- Saito, Kuniharu -- Raisler, Brian J -- Budd, Steven J -- Geisen, Pete -- Munitz, Ariel -- Ambati, Balamurali K -- Green, Martha G -- Ishibashi, Tatsuro -- Wright, John D -- Humbles, Alison A -- Gerard, Craig J -- Ogura, Yuichiro -- Pan, Yuzhen -- Smith, Justine R -- Grisanti, Salvatore -- Hartnett, M Elizabeth -- Rothenberg, Marc E -- Ambati, Jayakrishna -- AI039759/AI/NIAID NIH HHS/ -- AI45898/AI/NIAID NIH HHS/ -- DK076893/DK/NIDDK NIH HHS/ -- EY010572/EY/NEI NIH HHS/ -- EY015130/EY/NEI NIH HHS/ -- EY015422/EY/NEI NIH HHS/ -- EY017011/EY/NEI NIH HHS/ -- EY017182/EY/NEI NIH HHS/ -- EY017950/EY/NEI NIH HHS/ -- EY018350/EY/NEI NIH HHS/ -- EY018836/EY/NEI NIH HHS/ -- R01 DK076893/DK/NIDDK NIH HHS/ -- 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 EY018836-02/EY/NEI NIH HHS/ -- England -- Nature. 2009 Jul 9;460(7252):225-30. doi: 10.1038/nature08151. Epub 2009 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Science, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19525930" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Chemokine CCL11/antagonists & inhibitors/metabolism ; Chemokine CCL24/antagonists & inhibitors/metabolism ; Chemokines, CC/antagonists & inhibitors/metabolism ; Choroid/blood supply/cytology/metabolism ; Choroidal Neovascularization/diagnosis/metabolism ; Disease Models, Animal ; Endothelial Cells/cytology/metabolism ; Humans ; Inflammation ; Leukocytes ; Ligands ; Macular Degeneration/*diagnosis/metabolism/*therapy ; Mice ; Mice, Inbred C57BL ; Quantum Dots ; Receptors, CCR3/analysis/*antagonists & ; inhibitors/genetics/immunology/*metabolism ; Retina/drug effects/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-02-08
    Description: Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077055/" 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/PMC3077055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaneko, Hiroki -- Dridi, Sami -- Tarallo, Valeria -- Gelfand, Bradley D -- Fowler, Benjamin J -- Cho, Won Gil -- Kleinman, Mark E -- Ponicsan, Steven L -- Hauswirth, William W -- Chiodo, Vince A -- Kariko, Katalin -- Yoo, Jae Wook -- Lee, Dong-ki -- Hadziahmetovic, Majda -- Song, Ying -- Misra, Smita -- Chaudhuri, Gautam -- Buaas, Frank W -- Braun, Robert E -- Hinton, David R -- Zhang, Qing -- Grossniklaus, Hans E -- Provis, Jan M -- Madigan, Michele C -- Milam, Ann H -- Justice, Nikki L -- Albuquerque, Romulo J C -- Blandford, Alexander D -- Bogdanovich, Sasha -- Hirano, Yoshio -- Witta, Jassir -- Fuchs, Elaine -- Littman, Dan R -- Ambati, Balamurali K -- Rudin, Charles M -- Chong, Mark M W -- Provost, Patrick -- Kugel, Jennifer F -- Goodrich, James A -- Dunaief, Joshua L -- Baffi, Judit Z -- Ambati, Jayakrishna -- NIHU10EY013729/EY/NEI NIH HHS/ -- P30 EY006360/EY/NEI NIH HHS/ -- P30 EY014800/EY/NEI NIH HHS/ -- P30 EY014800-07/EY/NEI NIH HHS/ -- P30 EY021721/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- P30EY008571/EY/NEI NIH HHS/ -- P30EY06360/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-05/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-04/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY020672-02/EY/NEI NIH HHS/ -- R01 GM068414/GM/NIGMS NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY011123/EY/NEI NIH HHS/ -- R01EY015240/EY/NEI NIH HHS/ -- R01EY015422/EY/NEI NIH HHS/ -- R01EY017182/EY/NEI NIH HHS/ -- R01EY017950/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01GM068414/GM/NIGMS NIH HHS/ -- R01HD027215/HD/NICHD NIH HHS/ -- R21 EY019778/EY/NEI NIH HHS/ -- R21 EY019778-02/EY/NEI NIH HHS/ -- R21AI076757/AI/NIAID NIH HHS/ -- R21EY019778/EY/NEI NIH HHS/ -- RC1 EY020442/EY/NEI NIH HHS/ -- RC1 EY020442-02/EY/NEI NIH HHS/ -- RC1EY020442/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):325-30. doi: 10.1038/nature09830. Epub 2011 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21297615" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements/*genetics ; Animals ; Cell Death ; Cell Survival ; Cells, Cultured ; DEAD-box RNA Helicases/*deficiency/genetics/metabolism ; Gene Knockdown Techniques ; Humans ; Macular Degeneration/*genetics/*pathology ; Mice ; MicroRNAs/metabolism ; Molecular Sequence Data ; Oligonucleotides, Antisense ; Phenotype ; RNA/*genetics/*metabolism ; Retinal Pigment Epithelium/enzymology/metabolism/pathology ; Ribonuclease III/*deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    ERK1/2 activation is a therapeutic target in age-related macular degeneration (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-08-06
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    ERK1/2 in age-related macular degeneration [Medical Sciences] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-08-22
    Description: Deficient expression of the RNase III DICER1, which leads to the accumulation of cytotoxic Alu RNA, has been implicated in degeneration of the retinal pigmented epithelium (RPE) in geographic atrophy (GA), a late stage of age-related macular degeneration that causes blindness in millions of people worldwide. Here we show increased...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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