Reduction of pathological retinal neovascularization, vessel obliteration and artery tortuosity by PEDF protein-based therapeutic in an oxygen-induced ischemic retinopathy rat model

Abstract

Retinopathy of prematurity (ROP) is a worldwide severe disease which can lead to visual impairment or even blindness. It is characterized by obliteration of retinal vessels, presence of tortuous vessels and pathological neovascularization in the retina. The current treatments, cryotherapy, laser ablation or intravitreal injection of anti-VEGF produce limited effect and ineluctable complications. There is therefore still a high medical need for alternative, efficient and safer therapies. Pigment epithelium-derived factor (PEDF), a potent angiogenesis inhibitor, appears late in gestation and its lack may contribute to ROP. Using an ex vivo model of ischemia and an in vivo model of choroidal neovascularization, we recently discovered that PEDF protein inhibited pathological neovascularization by protecting the endothelial cells which subsequently enhanced the survival of neural retinal cells and photoreceptors respectively. Here we examined the effect of PEDF protein alone or in combination with anti-VEGF drugs and compared their efficacy after a single intravitreal injection in an oxygen-induced ischemic retinopathy (OIR) rat model. PEDF protein alone or in combination with anti-VEGFs significantly suppressed the pathological neovascularization and reduced vessel obliteration compared to anti-VEGF drugs alone demonstrating that the treatment inhibited pathological neovascularization but not physiological angiogenesis. Importantly, PEDF protein-based therapeutics significantly reduced the artery tortuosity indicating an improvement of the retinal vasculature’s quality. No functional or histological side-effects were found in rat eyes after intravitreal protein injection even at high dose. Thus, the use of PEDF protein alone or combined with anti-VEGF is beneficial, and is a promising therapeutic for ROP.