Drugs designed to act on the brain often come to grief at the blood-brain barrier. The effective purpose of the barrier, found in all vertebrates, is to protect the brain from harmful substances in the circulation. It explains why particularly large molecules such as proteins have up to now only rarely been considered as drugs for brain diseases. Penzberg researchers working with neuroscientist colleagues in Basel have come up with a way to make the blood-brain barrier more permeable to proteins.
A key component of the barrier consists of endothelial cells lining the blood vessel lumen and linked together by tight junctions of transmembrane proteins. The Penzberg researchers are using transcytosis, a naturally occurring mechanism for transporting certain large molecules through a cell: the molecule is packaged on one side of the cell into a vesicle, transported through the cell, then expelled on the other side.
Transferrin is one such molecule that benefits from transcytosis. pRED researchers are using an antibody against the transferrin receptor as a shuttle and coupling it to a protein with therapeutic activity: like transferrin, this complex molecule is then transported into the brain through the endothelial cell without being degraded on the way. In the Alzheimer mouse model, the researchers have used this technique to increase the rate of uptake more than 50 fold. Should these results be confirmed, this would be an enormously important step towards effective treatment of a wide range of brain diseases, with a minimum of side effects.