Wnt Pathway Agonism as a Therapeutic Strategy for Retinal Vascular Diseases: A Narrative Review of Evidence to Date

Breakdown of the blood-retinal barrier (BRB) is implicated in many blinding retinal diseases, including diabetic macular edema, neovascular age-related macular degeneration, and retinal vein occlusion. Anti-vascular endothelial growth factor (anti-VEGF) therapies or laser photocoagulation are currently the standard of care for retinal diseases that are characterized by breakdown of the vascular barrier function and vascular hyperpermeability. However, inadequate response to anti-VEGF therapy is seen in a substantial proportion of patients and laser photocoagulation does not restore vision loss and can lead to collateral damage of the retina. Thus, new therapeutic targets are needed. The β-catenin-dependent wingless-related integration site (Wnt) signaling pathway plays a critical role in inner BRB development and maintenance. There are several potential therapeutics for retinal vascular diseases targeting the Wnt/β-catenin pathway under investigation, including several in preclinical development and one (MK-3000; also known as Restoret and formerly EYE103) with early clinical trial results advancing to late-stage clinical development. In this narrative review we examine the role of Wnt/β-catenin signaling in inner BRB maintenance and in retinal vascular diseases, as well as the potential for Wnt pathway agonism as a therapeutic approach.