Ref-1 is overexpressed in neovascular eye disease and targetable with a novel inhibitor

Area of Science:

• Ophthalmology
• Molecular Biology
• Biochemistry

Background:

• Reduction-oxidation factor-1 (Ref-1/APE1) is a redox-sensitive transcription factor activator implicated in ocular neovascularization.
• Key neovascular eye diseases like neovascular age-related macular degeneration (nAMD) involve inflammation and angiogenesis, processes potentially regulated by Ref-1.
• Previous studies indicated Ref-1's role in ocular endothelial cell growth and choroidal neovascularization (CNV).

Purpose of the Study:

• To further investigate the role of Ref-1 in neovascular eye diseases.
• To assess the therapeutic potential of inhibiting Ref-1's redox function in models of ocular neovascularization.

Main Methods:

• Quantification of Ref-1 expression in human nAMD and murine neovascularization models (laser-induced CNV, Vldlr-/- SRN).
• Demonstration of Ref-1 interaction with the inhibitor APX2009 using NMR and docking.
• Evaluation of APX2009's efficacy in vitro on endothelial cells and in vivo in murine models of L-CNV and SRN.

Main Results:

• Ref-1 was highly expressed in human nAMD and murine neovascularization models.
• The small molecule inhibitor APX2009 effectively blocked angiogenic features in endothelial cells.
• Intravitreal APX2009 ameliorated laser-induced CNV, while systemic APX2009 reduced subretinal neovascularization and downregulated CA9 expression in Vldlr-/- mice.

Conclusions:

• The redox function of Ref-1 is a critical regulator of ocular angiogenesis.
• Inhibition of Ref-1, demonstrated by APX2009, holds significant therapeutic potential for treating nAMD and other neovascular eye conditions.