From Spider Webs to Brains: Can the Bri2 BRICHOS Molecular Chaperone Domain Transport Biological Drugs Into the...

Biological drugs like antibodies or enzymes have very limited access to the central nervous system (CNS) because the blood-brain barrier (BBB) excludes macromolecules that are not required for brain homeostasis. To overcome this hurdle, different types of shuttle systems have been designed, such as linking the drugs to binders to transporters present in the BBB, thereby allowing receptor-meditated transcytosis (RMT), or encapsulating them in liposomes that have been modified to promote RMT and/or adsorptive-mediated transcytosis. These shuttles have given encouraging results but are at the same time associated with potential drawbacks like risk of interfering with transport of the endogenous ligands, immune responses and limited efficiencies to deliver the cargo drugs further to intracellular targets. BRICHOS is a 14 kDa protein domain present in ten human protein families and apparently specialised to prevent amyloid toxicity. Recent studies have shown that recombinant BRICHOS from the Bri2 protein can be used to transcytose model cargo protein from spider silk over vascular endothelial cells and promote endocytosis into neurons in the CNS of mice. Here, the potential of harnessing recombinant Bri2 BRICHOS for the transport of biological drugs into the CNS parenchyma and cells is discussed.