Strategies To Overcome Blood-brain Barrier

"The blood-brain barrier issue probably serves as the most significant roadblock to the treatment of central nervous system diseases," says John Sterling, Editor in Chief of GEN. "The key challenge is to treat people suffering from CNS disorders while trying to stay true to the physician's oath, 'First do no harm'."

One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).

In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson's disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.

Another major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).

In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.

Among the companies and academic centers covered in the GEN blood-brain barrier article are Pfizer, Lilly, Bristol-Myers Squibb, Otsuka, GlaxoSmithKline, Xenoport, ArmaGen, UCLA, Leiden University, and The Immune Disease Institute at Harvard Medical School.