APE1/Ref-1 as a Novel Target for Retinal Diseases

Curtis Heisel; Jonah Yousif; Mahmut Mijiti; Kostas Charizanis; Mitchel Brigell; Timothy W Corson; Mark R Kelley

doi:10.33696/Signaling.2.044

APE1/Ref-1 as a Novel Target for Retinal Diseases

J Cell Signal. 2021;2(2):133-138. doi: 10.33696/Signaling.2.044.

Authors

Curtis Heisel¹, Jonah Yousif¹, Mahmut Mijiti², Kostas Charizanis³, Mitchel Brigell⁴, Timothy W Corson^{5

6

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8}, Mark R Kelley^{2

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6

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8}

Affiliations

¹ University of Michigan Medical School, 1301 Catherine St, Ann Arbor, MI 48105, USA.
² Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
³ Kostas Charizanis, Independent Consultant, Livonia, MI 48150, USA.
⁴ Ocuphire Pharma Inc., Farmington Hills, MI, USA.
⁵ Department of Pharmacology and Toxicology, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
⁶ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
⁷ Indiana University Simon Comprehensive Cancer Center, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.
⁸ Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN 46202, USA.

Abstract

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].

Keywords: APE1/Ref-1; Angiogenesis; Apurinic/apyrimidinic endonuclease; Choroid; Inflammation; Neovascularization; Ocular clinical trial; Redox effector factor 1; Redox signaling; Retina; Transcription factors.

Abstract

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