CNS drug delivery by identifying small molecule inhibitors of a newly identified key regulator of the blood brain barrier

A major obstacle in treating neurological diseases and brain tumors is to deliver drugs or antibodies across the ‘blood brain barrier’ (BBB). My lab’s discoveries have changed our understanding of how the BBB restricts blood-brain communication1-4. The BBB is formed by a single layer of endothelial cells that lines the blood vessel walls and act as a gatekeeper for the brain. Historically, the restricted permeability of brain vasculature has been attributed to tight junctions5. However, substances can also cross endothelial cells by transcytosis, and we discovered that transcytosis is actively inhibited in brain endothelial cells. We identified a novel multi-transmembrane protein Mfsd2a as a key regulator for BBB function, and demonstrated that interfering with Mfsd2a and its downstream pathway upregulates transcytosis and causes the BBB to become permeable1-3. We propose to develop small molecule inhibitors as therapeutic agents that specifically target Mfsd2a function as a strategy to facilitate drug delivery across the BBB.