Abstract
Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.
Highlights
Angiogenesis, the division and proliferation of endothelial cells, causes an increase in blood vessel growth
Retinal neovascularization occurs in proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP), while choroidal neovascularization occurs in neovascular age-related macular degeneration (nvAMD)
APE1/redox effector factor 1 (Ref-1) redox signaling modulates HIF-1-mediated CA9 expression. This relationship has not been conclusively shown in the eye, previous studies revealed that reduction of APE1/Ref-1 redox signaling with APX3330 reduces CA9 expression in pancreatic ductal adenocarcinoma cells (PDAC) cells, demonstrating that APE1/Ref-1 contributes to HIF-1-mediated transcription [74]
Summary
Angiogenesis, the division and proliferation of endothelial cells, causes an increase in blood vessel growth. APE1/Ref-1 reduces transcription factors to activate their DNA binding, while APE1/Ref-1 becomes oxidized and forms disulfide bonds between cysteine residues This thiol/sulfide exchange affects gene expression and protein synthesis driven by several TFs, including NF-κB, HIF-1α, STAT3, Nrf and others [9,17] (Figure 1A). Use of APE1/Ref-1 redox inhibitor APX3330 resulted in an increase in DNA repair activity of APE1/Ref-1 in rats, which reduced neurotoxic effects induced by CIPN [89,90]. Given APE1/Ref-1 s role in oxidative stress response in PD, AD, ALS, cerebral ischemia and sensory neuropathy, it is evident that APE1/Ref-1 modulates a wide variety of disease states via various pathways Factors such as AP-1, HIF-1α, NF-κB and STAT3 have been implicated in irritable bowel disease (IBD). APE1/Ref-1 has been implicated elsewhere in cardiovascular disease and in gastric cellular response to Helicobacter pylori infection [17,65]
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