CNS Drug Developers Struggle To Overcome Blood Brain Barrier

Haberman, Ph.D., founder and principal of Haberman Associates (Boston, MA, USA), in the February 1, 2009, issue of the journal Genetic Engineering and Biotechnology News has reviewed the current state of the art and discussed the various approaches used by researchers to induce drug molecules to cross the BBB.

While more than 98% of small molecules are prevented from entering the brain by the BBB, some molecules of molecular weight less than 400 Daltons have been found that will cross the barrier. However, successfully crossing into the brain does not mean that the drug will be effective. Brain cells are also protected by the action of efflux transporters. These are adenotriphosphate- (ATP)-dependent membrane glycoproteins that actively expel molecules that have crossed the BBB back across endothelial cell membranes and out of the brain. The most important efflux transporter is P-glycoprotein (P-gp). Thus, a successful low molecular weight drug must both cross the BBB by passive transport (diffusion) while being a poor substrate for P-gp.

In addition to passive transport, researchers have tried carrier-mediated transport (CMT) to move small molecules across the BBB. For this method to work, the candidate drug must be configured to mimic a metabolite that is naturally transported across the BBB. The best-known example is L-DOPA, the major current drug for Parkinson's disease. L-DOPA replaces the dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.

Larger molecules such as peptides and proteins cannot cross the BBB by passive transport. The main route available for such large molecules to cross the barrier is by receptor-mediated transport (RMT). The drug molecule must first bind specific receptor proteins on brain capillaries in order to be transported through the cell membrane and into brain endothelial tissue. Examples of large molecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).

Most drug developers in the CNS field agree that bridging the BBB is the major challenge to finding novel CNS drugs. Academic and corporate researchers are developing technologies that may enable the design of small and large molecule drugs that are actively transported across the BBB. Tests of the feasibility of these technologies are currently being carried out in animal studies.

Haberman Associates is a consulting firm that specializes in science and technology strategy for life-science companies.

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