Blood-brain barrier function in drug delivery and neurodegenerative disease
The blood-brain barrier (BBB)—formed by the endothelial cells lining the cerebral microvessels—acts as a regulatory interface controlling the influx and efflux of molecules in the central nervous system (CNS). There have been significant advances in understanding the molecular factors governing transport of xenobiotics (including drugs) across the BBB. However, how these processes alter in neurodegenerative diseases—including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis—remains to be characterised.
A major research focus for D4 is to understand how alterations at the BBB in animal models of these diseases—including changes to membrane transporters and intracellular carrier proteins—impact on drug distribution into the CNS. This research provides insight into whether preclinical studies assessing BBB penetration of novel drug candidates in healthy mice are an accurate representation of that expected in mouse models of disease (and therefore patients).
Furthermore, this research explores whether people with such neurodegenerative diseases are at altered risk of CNS exposure (and toxicity) of the many other medicines they are taking—which may otherwise exhibit minimal BBB transport under healthy conditions.
While the BBB restricts entry of many xenobiotics into the CNS, it also acts as the port of exit of the many agents that must be cleared from the brain. Various efflux transporters are involved in the clearance of beta-amyloid—a protein that accumulates in the brains of people with Alzheimer's disease, and is held responsible for the associated cognitive deficits. The BBB expression of these efflux transporters is significantly attenuated in people with Alzheimer's disease.
D4's research is focusing on unravelling the mechanisms responsible for this down-regulation, while investigating approaches to enhance the expression and function of these transporters. Using a host of in vitro and in vivo transport and molecular studies, the aim of this research is to develop agents that can act directly at the BBB to enhance the clearance of beta-amyloid from the brain, resulting in the development of novel treatments for this debilitating neurodegenerative disease.