title: Topical application of a G-Quartet aptamer targeting nucleolin attenuates choroidal neovascularization in a model of age-related macular degeneration.
abstract: Choroidal neovascularization (CNV) associated with the 'wet' form of age related macular degeneration (AMD) is one of the most common causes of central vision loss among the elderly. The 'wet' form of AMD is currently treated by intravitreal delivery of anti-VEGF agents. However, intravitreal injections are associated with complications and long-term inhibition of VEGF leads to macular atrophy. Thus, there is currently an unmet need for the development of therapies for CNV that target molecules other than VEGF. Here, we describe nucleolin as a novel target for the 'wet' form of AMD. Nucleolin was found on the surface of endothelial cells that migrate from the choroid into the subretinal space in the laser-induced model of 'wet' AMD. AS1411 is a previously described G-quartet oligonucleotide that has been shown to bind nucleolin. We found that AS1411 inhibited the formation of tubes by human umbilical vein endothelial cells (HUVECs) by approximately 27.4% in vitro. AS1411 co-localized with the site of laser induced CNV in vivo. Intravitreally injected AS1411 inhibited laser-induced CNV by 37.6% and attenuated infiltration of macrophages by 40.3%. Finally, topical application of AS1411 led to a 43.4% reduction in CNV. Our observations have potential implications for the development of therapies for CNV and specifically for the 'wet' form of AMD.
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Leaderer
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
authors.forename: Siobhan M
authors.initials: SM
authors.lastname: Cashman
authors.affiliation: Department of Developmental, Molecular and Chemical Biology, Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA. Electronic address: Rajendra.Kumar-Singh@tufts.edu.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar-Singh
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000008:administration & dosage*; D002465:Cell Movement / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects; D006028:Glycosphingolipids / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D058449:Intravitreal Injections; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000378:metabolism / Q000517:prevention & control*; D000097796:Nucleolin
chemical_list: D000943:Antigens, Differentiation; D052157:Aptamers, Nucleotide; D006028:Glycosphingolipids; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100; C119144:glycosphingolipid GSL-1; C036763:monocyte-macrophage differentiation antigen
keywords: AS1411; Age-related macular degeneration (AMD); Aptamer; Laser-induced choroidal neovascularization (CNV); Nucleolin