An APE1 Redox Inhibitor Attenuates Pathological Retinal Vascularization by Suppressing FGF2 Angiogenic Signaling.

Abstract

PURPOSE: Retinal neovascular (RNVs) diseases are major causes of visual loss. Current first-line therapies for RNV primarily target VEGF. However, intrinsic or acquired resistance to anti-VEGF therapy, along with the risks associated with repeated intraocular injections, underscores the need for alternative targets and new therapeutic strategies. Apurinic/apyrimidinic endonuclease 1 (APE1) regulates transcription factors implicated in RNV. The purpose of this study was to evaluate APE1 as a therapeutic target, assess the potential of its redox inhibitor, Refi-10, as a drug candidate for vascular retinopathies, and elucidate underlying mechanisms. METHODS: An oxygen-induced retinopathy (OIR) mouse model and the APE1 redox inhibitor Refi-10 were used to investigate the contribution of APE1 redox function in retinopathy neovascularization and assess the therapeutic efficacy of Refi-10. Transcriptomic analysis of OIR retinas identified pro-angiogenic factors and pathways associated with RNV and Refi-10-mediated improvement. Retinal pigment epithelium (RPE) and human retinal microvascular endothelial cells (hRMECs) were used to investigate cellular mechanisms and responses to Refi-10. RESULTS: Refi-10 significantly reduced pathological angiogenesis and ameliorated RNV disease. Mechanistic studies showed that Refi-10 attenuated inflammation and angiogenesis via APE1 inhibition. Notably, Refi-10 did not decrease retinal VEGF in OIR but mitigated RNV by suppressing fibroblast growth factor 2 (FGF2) expression. CONCLUSIONS: These findings nominate APE1 and FGF2 signaling as promising therapeutic targets, and show that Refi-10 holds potential as a drug candidate for vascular retinopathies, offering an alternative or complementary approach to VEGF inhibition.