VEGF‐TRAP_R1R2 suppresses choroidal neovascularization and VEGF‐induced breakdown of the blood–retinal barrier

Abstract

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF-TRAP(R1R2), in models for these disease processes. VEGF-TRAP(R1R2) is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF-TRAP(R1R2) strongly suppressed choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane. Subcutaneous injection of VEGF-TRAP(R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF-induced breakdown of the blood-retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF-TRAP(R1R2) significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF-TRAP(R1R2) may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice

“…The model is applicable to transgenic (knock-out or knock-in) mice. In addition, viruses, cells or compounds, including neutralizing antibodies, si/shRNA, pre-miR, recombinant proteins, nanoparticles and drugs, can be administered via different pathways (intraperitoneal injection, intravenous injection, per os, drinking water, intravitreous injection, subretinal injection, BM engraftment and others) and combined or not with genetic manipulation 9,[33][34][35][36][37] .…”

Vascular endothelial growth factor receptors: Molecular mechanisms of activation and therapeutic potentials

“…To date, the anti-angiogenesis therapy for ocular diseases that have been evaluated are angiogenesis inhibitors that mainly bind to VEGF such as pegaptanib (Macugen), and VEGFTrap (Saishin et al, 2003;Gragoudas et al, 2004;Zakarija and Soff, 2005). Pegaptanib and VEGF-Trap like Avastin bind to VEGF and prevent binding of VEGF to VEGF receptors.…”

Potential applications for RNAi to probe pathogenesis and develop new treatments for ocular disorders

“…Several previous studies had demonstrated that vascular endothelial growth factor (VEGF) is a critical stimulus for choroidal neovascularization. [5][6][7] Reich et al 8 tested the feasibility of targeting VEGF in vivo with siRNA directed against Vegf mRNA in two ways. Mice received a subretinal injection of adenoviral vector containing a CMV promoter coupled to hVegf cDNA in both eyes combined with siRNA directed against hVegf mRNA in one eye and siRNA directed against green fluorescent protein (GFP) mRNA in the other eye.…”