title: Antagonism of PDGF-BB suppresses subretinal neovascularization and enhances the effects of blocking VEGF-A.
abstract: Hypoxia-inducible factor-1 (HIF-1) plays an important role in retinal and subretinal neovascularization (NV). Increased levels of HIF-1 cause increased expression of vascular endothelial growth factor (VEGF-A) and current therapies for ocular NV focus on neutralizing VEGF-A, but there is mounting evidence that other HIF-1-responsive gene products may also participate. In this study, we tested the effect of a designed ankyrin repeat protein (DARPin) that selectively binds and antagonizes the hypoxia-regulated gene product PDGF-BB in three models of subretinal NV (relevant to neovascular age-related macular degeneration) and compared its effects to a DARPin that selectively antagonizes VEGF-A. Daily intraperitoneal injections of 10 mg/kg of the anti-PDGF-BB DARPin or 1 mg/kg of the anti-VEGF DARPin significantly suppressed subretinal NV from laser-induced rupture of Bruch's membrane. Injections of 1 mg/kg/day of the anti-PDGF-BB DARPin had no significant effect, but when combined with 1 mg/kg/day of the anti-VEGF-A DARPin there was greater suppression than injection of the anti-VEGF-A DARPin alone. In Vldlr (-/-) mice which spontaneously develop subretinal NV, intraocular injection of 1.85 μg of anti-PDGF-BB or anti-VEGF-A DARPin caused significant suppression of NV and when combined there was greater suppression than with either alone. The two DARPins also showed an additive effect in Tet/opsin/VEGF double transgenic mice, a particularly severe model of subretinal NV and exudative retinal detachment. In addition, intraocular injection of 1.85 μg of anti-PDGF-BB DARPin strongly suppressed ischemia-induced retinal NV, which is relevant to proliferative diabetic retinopathy and retinopathy of prematurity. These data demonstrate that PDGF-BB is another hypoxia-regulated gene product that along with VEGF-A contributes to ocular NV and suppression of both provides an additive effect.
authors.affiliation: Departments of Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Aling
authors.initials: A
authors.lastname: Dong
authors.forename: Christopher
authors.initials: C
authors.lastname: Seidel
authors.forename: Daniel
authors.initials: D
authors.lastname: Snell
authors.forename: Savira
authors.initials: S
authors.lastname: Ekawardhani
authors.forename: Julia K J
authors.initials: JK
authors.lastname: Ahlskog
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwase
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stevens
authors.forename: Sean F
authors.initials: SF
authors.lastname: Hackett
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stumpp
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000818:Animals; D000077214:Becaplermin; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000473:pathology; D056965:Injections, Intraocular; D007511:Ischemia / Q000150:complications / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D055355:Opsins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012163:Retinal Detachment / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D055355:Opsins; D020574:Proto-Oncogene Proteins c-sis; D011973:Receptors, LDL; D011993:Recombinant Fusion Proteins; C036053:VLDL receptor; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin