Restoration of the Inner Blood–Retinal Barrier in Diabetic Retinopathy Through Norrin-FZD4 Signaling

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in the working-age population and is characterized by the disruption of the blood–retinal barrier (BRB) integrity and increased vascular permeability. Elevated vascular endothelial growth factor (VEGF) contributes to BRB dysfunction in DR. Current therapies for DR, including anti-VEGF agents, have provided significant clinical benefits; however, not all patients respond optimally, highlighting the need for new therapeutic approaches. Norrin, an endogenous cytokine essential for blood–retinal barrier development and maintenance, has emerged as a potential therapeutic target for restoring barrier function in retinal vascular disease. In this review, we summarize the evidence supporting norrin signaling as a mechanism for restoring BRB properties following VEGF-induced barrier disruption and in DR, as well as its role in preserving visual function. We also discuss the development of engineered FZD4 agonists designed to mimic or enhance norrin signaling, providing a therapeutic strategy to activate this pathway independently of endogenous norrin. Together, these findings highlight norrin-FZD4 signaling as a potential therapeutic approach to restore BRB integrity and preserve vision in DR and other blinding diseases associated with BRB dysfunction.