Low Dose or Transient Administration of VEGF Trap Suppresses Corneal Neovascularization and Inflammation

Abstract

Abstract: : Purpose: To evaluate the efficacy of VEGF Trap (a potent VEGF inhibitor comprising portions of the ligand binding domains of VEGF receptors 1 and 2 coupled to human Fc), given at low doses or transiently, on the development of neovascularization in two animal models of corneal injury. Methods: Corneal neovascularization was induced by intrastromal placement of nylon sutures or by chemical (alkali) injury in male C57BL/6 mice. In the suture model, VEGF Trap was given subcutaneously (sc) at 1.0, 2.5 or 10 mg/kg on days 0, 4, 7 and 10 following injury and the corneas were evaluated on day 13. In the chemical injury model, VEGF Trap was administered at 12.5mg/kg (sc) on days 5 and 12 after chemical injury and the corneas were evaluated on days 42 and 70. For both studies, the vasculature was labeled by intravenous injection of fluorescein–conjugated lectin (lycopersicon esculentum) and the extent of neovascularization was quantified in corneal flat–mounts using the Scion Image program. Corneal edema was evaluated by slit lamp microscopy and corneal thickness was measured in cross–sections. Polymorphonucleocytes (PMN) and macrophages were counted in sections stained with HEMA–3 or F4/80 antibody, respectively. Results: In the suture injury model, administration of VEGF Trap at all doses tested significantly inhibited corneal neovascularization compared to controls. Following chemical injury, delayed and transient treatment with the VEGF Trap (days 5 and 12) significantly decreased corneal neovascularization for at least 30 days following the last injection (p<0.01, compared to controls on day 42). Corneal edema and the infiltration of PMNs into the damaged corneas also were substantially reduced in VEGF Trap treated animals compared to vehicle treated controls, in both corneal injury models. Conclusions: Systemic administration of VEGF Trap suppresses the development of corneal neovascularization, edema and inflammation following injury, even when delivered at low doses. At somewhat higher doses, treatment for a brief period following injury can exert relatively prolonged beneficial effects. These findings suggest that pharmacological inhibition of VEGF may be useful in the treatment of neovascularization and inflammation following corneal injury.

Keywords: growth factors/growth factor receptors • inflammation • neovascularization