BIBF1120 (Vargatef) Inhibits Preretinal Neovascularization and Enhances Normal Vascularization in a Model of Vasoproliferative Retinopathy

PURPOSE. This study evaluated the effects of BIBF1120, a novel triple angiokinase inhibitor against pathological retinal neovascularization. METHODS. BIBF1120 effect on development of the normal retinal vasculature was evaluated in Sprague-Dawley rat pups. Two models of ischemic oxygen-induced retinopathy (OIR) and the aortic ring assay were used to assess the antiangiogenic effects of BIBF1120. In the vaso-obliteration model (VO), rat pups were exposed to 80% O-2 from postnatal day (P) 5 to P10. In the preretinal neovascularization (NV) model, rat pups were exposed to cycling O-2 (50% and 10%) from P1 to P14, followed by room air until P18. Animals were intravitreally or orally treated with BIBF1120. Retinal vasculature, VO, and NV were evaluated in retinal flat mounts. Retinal expression of VEGF, Delta-like ligand 4 (Dll4), Netrin-1, Ephrin-B2, and EphB4 was analyzed by quantitative PCR and Western blot analysis. RESULTS. BIBF1120 interfered with normal retinal vascular development and microvessel branching in the aortic assay. However, in VO model BIBF1120 did not accrue VO. On the contrary, in the NV model BIBF1120 accelerated normal retinal vascularization and robustly diminished preretinal neovascularization compared to vehicle (by similar to 80%). The expression levels of VEGF negative regulator Dll4 and repulsive cues EphrinB2 and EphB4 mRNA in the retina of vehicle-treated OIR animals were markedly increased compared to normoxia, but were normalized by BIBF1120. CONCLUSIONS. Data reveal efficacy of BIBF1120 on preretinal neovascularization and, of greater interest, on acceleration of normal vascularization, consistent with interference of major repulsive cues expressed in the retina during OIR. Accordingly, BIBF1120 appears to exhibit preferable properties compared to anti-VEGF therapies for the treatment of ischemic retinopathies.