Targeted drug delivery across the blood-brain barrier

This project will seek to develop a new strategy to target circulating drugs into the central nervous system (CNS) by enhancing their ability to cross the blood brain barrier (BBB). This will be accomplished by combining drugs with a targeting moiety directed against a novel surface receptor on CNS endothelial cells (ECs). After systemic administration, engagement of the endothelial target triggers receptor-mediated transcytosis of the associated payload across the BBB. To this end, we have generated a comprehensive atlas of endothelial gene expression in 20 different murine tissues, including the CNS. Preliminary experiments have identified a BBB associated surface protein as the primary candidate target. We have already produced novel nanobodies (NAbs) against a specific extracellular epitope of this target that recognize both murine and human orthologues. Here, we are requesting funding to further characterize these NAbs in vitro (aim 1) and in vivo (aim 2) and to demonstrate their utility as tissue specific vehicles for targeted delivery of existing FDA approved biologics to the CNS (aim 3).