Drug delivery beyond the Blood-Brain Barrier – BeyondBBB

The Blood-Brain Barrier (BBB) protects the brain from toxins and pathogens and maintains homeostasis and appropriate function of the central nervous system (CNS). However, the unchallenged impermeability of the BBB impedes drug and treatment delivery to the brain during various CNS pathologies. Hence, the development of tailored therapeutic strategies designed to “on-demand” increase BBB permeability is a major unmet clinical need to treat CNS diseases.

Our group identified the endothelial Unc5B receptor and its ligand Netrin-1 as a novel signaling pathway regulating BBB integrity. We developed and patented monoclonal antibodies (Anti-Unc5B-3) blocking Netrin-1 binding to Unc5B that can be delivered intravenously to foster transient BBB opening. We hypothesize that our BBB-permeabilizing approach can be used to deliver drugs beyond the BBB to treat patient suffering from diverse neurological diseases.

In this proposal, two French team and two additional collaborators with complementary expertise will join forces to (1) determine Anti-Unc5B-3 pharmacokinetic and pharmacodynamic properties, (2) characterize if acute or chronic Anti-Unc5B-3 mediated opening of the BBB induces toxicity or neurological damage and (3) determine which molecules can be shuttled beyond the BBB and which cell type can be targeted.

It is considered that 100% of large-molecule drugs and around 98% of small-molecule drugs do not cross CNS barriers. Of various approaches under development to increase brain drug delivery, none are as easy to administer, non-invasive and brain wide as the Anti-Unc5B-3 therapy we developed. This proposal will increase our current understanding of how Anti-Unc5B-3 mediated BBB opening can be leveraged to deliver drugs, paving the way for novel therapeutic perspectives and giving a second life to FDA-approved and off-patent drugs, which will be investigated in follow-up proposal.