MiR-23b Neutralization In Brain Endothelium Promotes Blood-Brain Barrier Repair Through Wnt/Beta-catenin Dependent And Independent Mechanisms

Objective: Disruption of the blood-brain barrier (BBB) is an early and critical event in the pathogenesis of stroke and other central nervous system (CNS) disorders. Yet, therapeutic strategies to restore BBB integrity remain limited. Approach and Results: Using an unbiased anti-miR library screen, we identify miR-23b as a negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b with anti-miR -23b in BECs enhances junction protein expression, suppresses transcellular transport, and improves barrier function via Wnt/β-catenin-dependent and -independent mechanisms. In a 3D microfluidic model, anti-miR-23b accelerates vessel maturation, enhances resilience to ischemic injury, and facilitates BBB repair. AAVBR1-mediated delivery of anti-miR-23b to brain endothelium reduces BBB leakage, infarct volume, neurological deficits, and mortality in the rodent transient middle cerebral artery occlusion (tMCAo). Conclusion: Thus, miR-23b is a critical regulator of cerebrovascular integrity, and anti-miR-23b may be a promising novel RNA-based therapeutic to enhance BBB repair in stroke and other CNS disorders.