Wanted: A Therapy That Knows No Barrier

You know things that slip across the blood-brain barrier because you can feel their effects—alcohol, aspirin, the active stuff in cough medicine. But more often than not, foreign molecules can’t traverse this barricade of the brain and spinal cord—a source of frustration to those looking to treat diseases like Alzheimer’s, brain tumors or ALS.

Scott Banta (left) says small peptides may do the trick.

Often called the “BBB,” the barrier’s actually the wall of the capillaries that penetrate the central nervous system, along with tightly nestled nearby cells. A marvel of structure and function, the barrier keeps toxins and other molecular lowlifes away from precious brain and spinal tissues while letting necessary nutrients and gases through. The problem, however, comes when disease strikes and the barrier excludes therapeutic drugs.

Though pharmaceutical companies and others know the barrier well, scant work exists on overcoming it. Last summer, however, the Packard Center began systematic moves to breach the BBB in the name of treatment. Joining with three neuro-disease organizations—Accelerate Brain Cancer Cure (ABC2), the Michael J. Fox Foundation for Parkinson’s Research and the Alzheimer’s Association—we helped form the Brain Trust Collaborative. It’s just awarded its first two grants for promising approaches.

The project was propelled by a 2003 conference ABC2 sponsored to pinpoint obstacles to therapies. Brainstorming for two days, high-energy researchers in neurodegenerative disease and cancer singled out a dozen aspects to improve, things like better clinical trials design, better animal models, and more detailed databases.

“But the one that touched all the disorders,” says Packard Director Jeffrey Rothstein, “was the problem of the blood-brain barrier. Though each organization focuses on a distinct neurological disease and though therapies each might use wouldn’t necessarily overlap,” he says, “we all need to reach the central nervous system.”

One grant was given to Columbia University biochemical/ biomedical engineers Scott Banta and Barclay Morrison III. They’ve been investigating small protein segments— peptides—mysteriously capable of crossing the BBB. “We doubt that nature uses the small peptides for this purpose, and we really don’t know how they work,” says Banta, “but we know they can deliver ‘cargo’ into the brain. The difficult part is identifying peptides that can both penetrate the barrier and enter a specific cell.”

Such an approach might be able to target ALS patients’ motor neurons, for example, or the glial cells that support them. And the system Banta envisions could carry genes as well as drug molecules across.

With the grant, the researchers will set up an ingenious screening system for peptides that uses a lab-engineered sheet of BBB and a cultured brain slice. “Those that cross the barrier and into specific brain cells,” says Banta, “are the ones we want.”

Next > When Research Gets Personal
This summer, an unusual twosome worked together in a Packard Center lab.