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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.

APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: " The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease" by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer [1]. Previous studies have demonstrated that Ref-1 plays a critical role in regulating specific transcription factors (TFs) involved in a number of pathways, not only in cancer, but other disease indications as well. Disease indications of particular therapeutic interest include retinal vascular diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular age-related macular degeneration (nvAMD). While Ref-1 controls a number of TFs that are under redox regulation, three have been found to directly link cancer studies to retinal diseases; HIF-1α, NF-κB and STAT3. HIF-1α controls the expression of VEGF for angiogenesis while NF-κB and STAT3 regulate a number of known cytokines and factors involved in inflammation. These pathways are highly implicated and validated as major players in DR, DME and AMD. Therefore, findings in cancer studies for Ref-1 and its inhibition may be translated to these ocular diseases. This report discusses the path from cancer to the potential treatment of retinal disease, the Ref-1 redox signaling function as a possible target, and the current small molecules which have been identified to block this activity. One molecule, APX3330, is in clinical trials, while the others are in preclinical development. Inhibition of Ref-1 and its effects on inflammation and angiogenesis makes it a potential new therapeutic target for the treatment of retinal vascular diseases. This commentary summarizes the retinal-relevant research that built on the results summarized in the review by Caston et. al. [1]., Competing Interests: Conflict of Interest CH and JY conducted internships at Ocuphire Pharma, KC is an independent consultant, MB is head of clinical development and strategy at Ocuphire Pharma and MRK is a member of the Ocuphire medical advisory board and CSO and co-founder of Apexian Pharmaceuticals which developed APX3330 for oncology. TWC and MRK are inventors on patent applications licensed to Ocuphire. MM has no conflicts.

In the realm of DNA repair, base excision repair (BER) protein, APE1/Ref-1 (Apurinic/Apyrimidinic Endonuclease 1/Redox Effector - 1, also called APE1) has been studied for decades. However, over the past decade, APE1 has been established as a key player in reduction-oxidation (redox) signaling. In the review by Caston et al. ( The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease), multiple roles of APE1 in cancer and other diseases are summarized. In this Review, we aim to expand on the contributions of APE1 to various diseases and its effect on disease progression. In the scope of cancer, more recent roles for APE1 have been identified in cancer cell metabolism, as well as chemotherapy-induced peripheral neuropathy (CIPN) and inflammation. Outside of cancer, APE1 signaling may be a critical factor in inflammatory bowel disease (IBD) and is also an emergent area of investigation in retinal ocular diseases. The ability of APE1 to regulate multiple transcription factors (TFs) and therefore multiple pathways that have implications outside of cancer, makes it a particularly unique and enticing target. We discuss APE1 redox inhibitors as a means of studying and potentially combating these diseases. Lastly, we examine the role of APE1 in RNA metabolism. Overall, this article builds on our previous review to elaborate on the roles and conceivable regulation of important pathways by APE1 in multiple diseases., Competing Interests: Conflict of Interest MRK is a member of the Ocuphire medical advisory board and CSO and co-founder of Apexian Pharmaceuticals which licensed APX3330 and other APX compounds from Indiana University School of Medicine. Ocuphire Pharma licensed APX3330 for ocular and diabetes indications from Apexian Pharmaceuticals.