Purpose: Age-related macular degeneration (AMD) is the major cause of blindness for people over 60. In the ?wet? form of AMD, VEGF is a major determinant of choroidal neovascularization (CNV) and compounds targeting VEGF signaling have been a major focus for therapeutic interventions. We previously developed a rat model of CNV and have used this model to examine the ability of AG013764 and AG013711 (Pfizer) to reduce VEGF-induced CNV. Methods: AAV-VEGF165 was injected into subretinal space of rats at postnatal days 16-18. Six weeks later, suspension of AG013764 and AG013711 were injected intraperitoneally (IP, twice daily) or intravitreally (every five days) over a two week period. FITC-dextran whole-mounts of RPE-choroid-sclera were prepared after the animals were sacrificed. CNV area was quantified using Neurolucida. Data from intravitreal and intraperitoneal injections were analyzed by a Wilcoxon signed rank test and a Mann Whitney test, respectively. Histology and immunohistochemistry were done as previously described. Results: VEGF expression in control and treated eyes were confirmed by immunohistochemistry. Intravitreal injections of AG013764 reduced the level of CNV by 16% to 100% (p< 0.005, median 75%) in 12 of 13 animals, compared to control. A similarly significant result was obtained in 11 of 12 animals following intravitreal injection of AG013711. In three groups of IP injected animals (8-10 eyes per group), AG013764 vs control, the median CNV level was reduced by 48% (p< 0.05) in the treated eye. In AG013711 treated animals, the median area of CNV was reduced by 46% compared to control. Histological sections show recovery of retinal morphology in treated eyes. Conclusions: These data indicate that both compounds reduce blood vessel proliferation in our AAV-VEGF165 model of CNV, whether they are delivered directly into the eye or systemically. This reduction in CNV area is most likely an underestimate since it does not reflect changes in volume.
| Wang, F E; Shi, G; Niesman, M R et al. (2007) Receptor tyrosine kinase inhibitors AG013764 and AG013711 reduce choroidal neovascularization in rat eye. Exp Eye Res 84:922-33 |
