Restoring compromised blood-retina-barrier integrity with Netrin-1 overexpression

The blood-retina barrier (BRB) protects retinal neuronal function and enables vision. A compromised, leaky BRB is a hallmark of vision-threatening retinal diseases such as diabetic retinopathy (DR) and wet age-related macular degeneration (AMD) that affect millions of persons worldwide. Strategies to enhance BRB integrity hold promise as therapeutic interventions to prevent vision loss. Previous studies identified Netrin-1 (NTN1) as a key regulator of BRB stability and revealed reduced Netrin-1 signaling in DR patients, suggesting that Netrin-1 supplementation could help preserve BRB function and prevent disease progression. Herein, we used inducible genetic NTN1 overexpression to investigate effects on BRB development and maintenance. We show that global NTN1 overexpression converted leaky vessels at the P5 angiogenic front into a non-leaky state. In pathological settings, NTN1 overexpression reinforced BRB integrity in oxygen-induced retinopathy (OIR), improving electroretinogram (ERG) amplitudes and rescued vascular leak in laser-induced choroidal neovascularization (CNV). NTN1 overexpression or Ntn1 knockout minimally and transiently affected retinal angiogenesis. Global Unc5b deletion phenocopied vascular leak observed in Ntn1 deficient retinas, while angiogenesis defects differed between Ntn1 and Unc5b knockouts. These findings establish Netrin-1 as a promising therapeutic target for preventing BRB breakdown in retinal vascular diseases and suggest that reinforcing the Netrin-1/Unc5b signaling pathway may provide a strategy to selectively stabilize the BRB.