Inhibition of pathological angiogenesis in oxygen-induced retinopathy by arginine depletion with ADI-PEG20.

Abstract

Pathological retinal neovascularization (RNV) is vision-threatening. We tested the efficacy of a stable form of arginine deiminase (ADI-PEG20), which has antioxidant and anti-inflammatory actions, as a novel therapy for pathological RNV using a model of oxygen-induced retinopathy (OIR). Neonatal C57BL/6J mice and nursing dams were maintained in 75 % oxygen or room air as control from postnatal day 7 (P7) to P12. Mice were then treated with intravitreal injections of ADI-PEG20 or control PEG20. On P17, eyes were collected for analysis of avascular area, retinal neovascularization (RNV), and vascular tip cell characteristics. Other pups treated with ADI-PEG20 or PEG20 were maintained through P30 and tested for visual acuity, neuronal function, and vascular tortuosity. Human retinal microvascular endothelial cell (HREC) spheroids were also examined for effects of ADI-PEG20 on sprouting. Treatment of OIR mice with ADI-PEG20 significantly reduced both avascular area and RNV, increased vascular tip cell formation, and improved their morphology, as compared to PEG20-treated controls. Further, tip cells in the sprouts in ADI-PEG20 treated spheroids had fewer filopodia-like extensions, in response to VEGF compared to control spheroids. Mice treated with ADI-PEG20 showed improved visual acuity and decreased vascular tortuosity compared to PEG20 controls. Retinal electroretinography revealed preservation of scotopic-b wave amplitude in ADI-PEG20 treated mice. ADI-PEG20 did not alter photopic-b wave or a wave amplitude. Hence, intravitreal injection of ADI-PEG20 offers a novel strategy for limiting pathological angiogenesis, promoting vascular repair, and preserving visual function in conditions of ischemic retinopathy.