title: The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease.
abstract: Blood vessel growth from preexisting vessels (angiogenesis) underlies many severe diseases including major blinding retinal diseases such as retinopathy of prematurity (ROP) and aged macular degeneration (AMD). This observation has driven development of antibody inhibitors that block a central factor in AMD, vascular endothelial growth factor (VEGF), from binding to its receptors VEGFR-1 and mainly VEGFR-2. However, some patients are insensitive to current anti-VEGF drugs or develop resistance, and the required repeated intravitreal injection of these large molecules is costly and clinically problematic. We have evaluated a small cyclic retro-inverted peptidomimetic, D(Cys-Leu-Pro-Arg-Cys) [D(CLPRC)], and hereafter named Vasotide, that inhibits retinal angiogenesis by binding selectively to the VEGF receptors VEGFR-1 and neuropilin-1 (NRP-1). Delivery of Vasotide via either eye drops or intraperitoneal injection in a laser-induced monkey model of human wet AMD, a mouse genetic knockout model of the AMD subtype called retinal angiomatous proliferation (RAP), and a mouse oxygen-induced model of ROP decreased retinal angiogenesis in all three animal models. This prototype drug candidate is a promising new dual receptor inhibitor of the VEGF ligand with potential for translation into safer, less-invasive applications to combat pathological angiogenesis in retinal disorders.
authors.affiliation: Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Jianxue
authors.initials: J
authors.lastname: Li
authors.affiliation: RxGen Inc., Hamden, CT 06517, USA. St. Kitts Biomedical Research Foundation, St. Kitts, West Indies.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: RxGen Inc., Hamden, CT 06517, USA. St. Kitts Biomedical Research Foundation, St. Kitts, West Indies.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Hu
authors.affiliation: AMP Pharm LLC, Hopkinton, MA 01748, USA.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Musso
authors.affiliation: Institute of Chemistry, University of São Paulo, São Paulo 05508, Brazil.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Giordano
authors.affiliation: University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.affiliation: University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.affiliation: University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. richard_sidman@hms.harvard.edu rpasqual@salud.unm.edu warap@salud.unm.edu.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D000818:Animals; D004351:Drug Resistance; D000882:Haplorhini; D006801:Humans; D020104:Immunophilins / Q000037:antagonists & inhibitors; D008268:Macular Degeneration / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use*; D057786:Peptidomimetics / Q000737:chemistry / Q000627:therapeutic use*; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: C000609901:Cys-Leu-Pro-Arg-Cys (1-5)-disulfide; D010456:Peptides, Cyclic; D057786:Peptidomimetics; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020104:Immunophilins