title: A Sema3C Mutant Resistant to Cleavage by Furin (FR-Sema3C) Inhibits Choroidal Neovascularization.
abstract: In age-related macular degeneration (AMD), abnormal sub retinal choroidal neovascularization (CNV) is a major cause of blindness. FR-sema3C is a point mutated form of semaphorin-3C that is resistant to cleavage by furin like pro-protein convertases (FPPC). We have found in previous work that FR-sema3C functions as an anti-angiogenic factor. In this study we investigated the possible use of FR-sema3C as an inhibitor of CNV. FR-sema3C inhibits VEGF as well as PDGF-BB signal transduction in endothelial cells and to less extent bFGF induced signal transduction using a mechanism that does not depend upon the binding of VEGF like the drugs that are currently the mainstay treatment for AMD. CNV was induced in eyes of C57 black mice by laser photocoagulation. Intravitreal injection of FR-Sema3C or aflibercept (VEGF-trap) was then used to inhibit CNV formation. Invading choroidal vessels were visualized a week later by injection of FITC-dextran into the circulation, followed by the measurement of the area of the invading blood vessels. Injection of 0.1 μg FR-Sema3C inhibited CNV by 55% (P<0.01) and was as effective as 5 μg aflibercept. FR-sema3C did not display any adverse effects on retinal function following its injection into eyes of healthy mice as assessed by optokinetic reflex (OKR) and Electro-retinogram (ERG) criteria. Furthermore, FR-sema3C did not induce apoptosis in the retina as determined by TUNEL nor was there any discernable structural damage to the retina as assessed by several immuno-histochemical criteria. Our results suggest that FR-sema3C could perhaps be used for the treatment of AMD, and that it may perhaps be of benefit to patients that do not respond well to current treatments relying on VEGF sequestering agents.
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Toledano
authors.affiliation: Second Hospital of Jilin University, Changchun, Jilin Province, P.R. China.|Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Huayi
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, United States of America.
authors.forename: Agustina
authors.initials: A
authors.lastname: Palacio
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Ziv
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Kessler
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, United States of America.|Department of Ophthalmology and Visual Sciences, University of Massachusetts School of Medicine, Massachusetts, United States of America.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Schaal
authors.affiliation: Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
authors.forename: Gera
authors.initials: G
authors.lastname: Neufeld
authors.affiliation: Department of Ophthalmology, RAMBAM Medical Center, Haifa, Israel.
authors.forename: Yoreh
authors.initials: Y
authors.lastname: Barak
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism*; D003911:Dextrans / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000031:analogs & derivatives; D045683:Furin / Q000378:metabolism* / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism* / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D003911:Dextrans; D011993:Recombinant Fusion Proteins; C543908:Sema3C protein, human; D039961:Semaphorins; D042461:Vascular Endothelial Growth Factor A; C015219:fluorescein isothiocyanate dextran; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D045683:Furin; D016650:Fluorescein-5-isothiocyanate