INTRAVITREAL INJECTION OF VASCULAR ENDOTHELIAL GROWTH FACTOR SMALL INTERFERING RNA INHIBITS GROWTH AND LEAKAGE IN A NONHUMAN PRIMATE, LASER-INDUCED MODEL OF CHOROIDAL NEOVASCULARIZATION

Abstract

In Brief Purpose To determine the safety and efficacy of small interfering RNA (siRNA) directed against vascular endothelial growth factor (VEGF) in a nonhuman primate model of laser-induced choroidal neovascularization (CNV). Methods Each animal received laser rupture of Bruch’s membrane to induce CNV in both eyes. Each animal was then randomized to receive 0.05 mL of either vehicle alone or VEGF siRNA at 70 μg, 150 μg, or 350 μg in both eyes by intravitreal injection. Eyes were monitored weekly by ophthalmic examination, color photography, and fluorescein angiography for 36 days after laser injury. Electroretinograms were measured at baseline and at 5 weeks after laser. CNV on fluorescein angiograms were measured for area and graded for clinically significant leakage in a standardized, randomized, and double-masked fashion on days 15, 22, 29, and 36 after laser. Results VEGF siRNA did not cause any change in electroretinographic, hemorrhage, inflammation, or clinical signs of toxicity. A single administration of VEGF siRNA significantly inhibited growth of CNV and attenuated angiographic leakage in a dose-dependent manner. Conclusion Intravitreal injection of VEGF siRNA is capable of inhibiting the growth and vascular permeability of laser-induced CNV in a nonhuman primate in a dose-dependent manner. This study demonstrates preclinical proof of a principle that supports proceeding to clinical studies of VEGF siRNA in patients with exudative age-related macular degeneration. Posttranscriptional gene silencing by small interfering RNA (siRNA) is emerging as a potent mechanism of gene suppression. In this study, the authors demonstrate the successful in vivo therapeutic application of siRNA against vascular endothelial growth factor in a nonhuman primate by inhibiting growth and leakage of subretinal neovascularization in this clinically relevant model of exudative macular degeneration. This study provides support for the potential use of siRNA against vascular endothelial growth factor in the treatment of exudative age-related macular degeneration.