David Begley

Exploring and exploiting the Blood-Brain Barrier

The blood-brain barrier (BBB) is the critical interface between the blood and the extracellular fluid compartment (ECF) of the central nervous system CNS. The BBB is formed I early fetal life by the small capillary blood vessels of the brain where the endothelial cells form tight junctions between themselves which effectively obliterates any free paracellular diffusive pathway across these blood vessels. In consequence all solute transport from blood to brain has to be transcellular. Most polar solutes have a very limited CNS penetration unless a specific transporter for them is expressed in the BBB.

Routes of transport across the BBB

The cerebral micro vascular endothelial cells are highly polarised with a different spectrum of solute transporters and ion channels expressed in the luminal and abluminal membranes. ABC efflux transporters are also expressed in the BBB and are able to actively extrude their substrates from the CNS against a concentration gradient and are powered by ATP hydrolysis. The BBB is a dynamic and reactive interface influenced by cells of the surrounding nervous tissue. This arrangement of cells is often referred to as the neurovascular cell-association or the neurovascular unit.

The neurovascular cell association forming the BBB

The BBB allows the CNS to maintain an extremely stable internal fluid environment which is essential for complex neuronal function. The stability of the brain internal environment is an absolute requirement for reliable synaptic communication between nerve cells. The BBB is also a protective barrier which shields the CNS from any neurotoxic substances which circulate in the blood. These neurotoxins may be naturally occurring metabolites or proteins or a multitude of xenobiotics which are injected in the diet or otherwise acquired from the environment.

The presence of the blood-brain barrier severely limits the penetration of many drugs and therapeutic agents into the CNS and thus presents a huge challenge to the pharmaceutical industry in the design of new chemical entities to treat central nervous disease.

Current Research

Research in Dr Begley's laboratory is directed towards understanding the fundamental function of the BBB as a dynamic regulatory interface between the blood and brain but in addition we work closely with the pharmaceutical industry to develop strategies for dug delivery to the brain. In this They are examining the physico-chemical properties of molecules which will determine their passive or active movement across the endothelial cells of the BBB and exploring vector systems for the delivery of difficult or large “biopharmamaceuticals” such as growth factors, peptides/proteins and enzymes across the BBB.

They are also currently working on drug delivery to the CNS in lysosomal storage diseases. These are a group of approximately 50 inherited metabolic disorders many of which are neuronopathic and result in severe neurological decline and death in the first quartile of life. They result from an absent or reduced activity in one of a number of lysosomal degradative enzymes which results in the cellular accumulation of an intermediate storage product. In the past few years treatments have been devised which consist of enzyme replacement therapy (ERT) where genetically engineered functional enzyme is infused intravenously. This enzyme can be taken up by body cells and restore the functional defect.

Unfortunately the enzymes do not cross the BBB in therapeutic quantity, if at all, and the neurological damage persists and progresses. Other treatments consist of small molecular weight therapies, the so called substrate reduction therapies (SRT) and chemical chaperones which reduce storage product formation or boost enzyme activity. It is critical to the development of new effective CNS treatments to understand how current treatments interact with the BBB. There is also evidence that the BBB may be damaged in these conditions due to storage or associated inflammation thus contribution to the CNS damage.

The group is also researching the use of nanoparticles and similar systems as vectors for drug delivery to the CNS and have active collaborations with Universities and Research Institutes in Frankfurt, Moscow and Padua.