JUSTBRAIN · Blood-brain barrier junctions as targets for paracellular drug delivery to the brain

To maintain homeostasis of the central nervous system (CNS) the blood-brain barrier (BBB) prevents the free transcellular passage of hydrophilic molecules from the blood into the CNS. Because of this, the BBB is now recognised as the major obstacle to the treatment of most neurological disorders, as it hinders the delivery of many potentially important therapeutic and diagnostic substances to the CNS. Previous approaches in improving drug delivery across the BBB, which have primarily aimed at highjacking the transcellular transport machinery that is dedicated to the selective transport of specific molecules across the BBB, have had limited success, especially with regard to large molecular weight drugs. Lack of knowledge on the molecular composition and function of cerebrovascular cell-to-cell junctions has hampered the development of safe strategies for paracellular drug delivery across the BBB until recently. Members of the JUSTBRAIN consortium have accumulated knowledge on the structure and function of BBB cell-to-cell junctions, identified endothelial signals controlling the expression of individual junctional proteins and have begun to develop approaches, which may either open or close BBB junctions. Using in vitro and in vivo BBB models and animal models of neurological disorders, where BBB opening may be therapeutic, JUSTBRAIN is dedicated to translate this basic knowledge into identifying an entire novel platform of drugable molecular targets that could be functionally modulated thus allowing to bypass the BBB via the paracellular route. By these means JUSTBRAIN expects to improve efficient delivery of large molecules into the CNS and thus to expand on diagnostic and therapeutic possibilities for neurological disorders.