Par Kévin Boyé
CRCN INSERM, Paris Cardiovascular Research Center
Blood-CNS barriers including the Blood-Brain Barrier (BBB) and the Blood-Retina Barrier (BRB) protect the CNS from toxins and pathogens and maintain homeostasis and proper function of the CNS. However, the unchallenged impermeability of the BBB and BRB impedes drug and treatment delivery to the brain during various CNS pathologies. Indeed, while neurological disorders are currently the second leading cause of death worldwide, the vast majority of the potential drugs developed for CNS pathologies cannot reach their targets behind CNS barriers. Hence, the development of tailored therapeutic strategies designed to “on-demand” increase or reduce BBB permeability is the holy grail of CNS diseases.
We identified the endothelial Unc5B receptor and its ligand Netrin1 as a novel signaling pathway regulating BBB integrity. We developed inducible endothelial-specific Unc5B deleted mice and patented monoclonal antibodies blocking Unc5B activation that can be delivered i.v and causes CNS barrier opening to bioactive molecules for 1h to 8h followed by neurovascular barrier resealing. Moreover, we showed that anti-Unc5B treatment induced increased chemotherapy delivery into glioblastoma bearing mice and led to reduced tumor size and increased tumor cells apoptosis, offers a promising avenue to optimize therapeutic approaches of brain tumors.