These days, researchers unraveling the workings of the brain’s filter are trying to find similar kinds of passageways so they can get drugs past it too. Pardridge and his colleagues wondered if they could slip therapeutic compounds into the brain with the help of insulin and transferrin, a molecule that moves iron from place to place; both insulin and transferrin are granted free passage across the blood-brain barrier. To turn ordinary insulin and transferrin into Trojan Horses that can sneak other molecules inside, they engineered antibodies that could grab onto them. Next they welded drugs onto the antibodies.
In one experiment last year, the team attached erythropoietin, a compound that can help heal injured cells. They then injected the antibody-erythropoietin combination into the bloodstream of mice. The compound molecules made their way to the mice’s brains. There, the antibody was caught by transferrin transporters, which drew it—along with the erythropoietin—through the blood vessel walls and into the brain.
In May researchers at the biotech company Genentech unveiled another way to trick the brain into letting down its guard. Instead of attaching a drug to an antibody, they made the antibody itself their drug. The group exploited the fact that antibodies are shaped roughly like the letter Y, with the two arms able to latch onto proteins. Which kind of protein they grab depends on the particular nooks and crannies in each arm. The Genentech researchers engineered one of the arms to seize a receptor that normally snags transferrin. With the receptor in tow, the antibody was able to pass through the blood-brain barrier. Once it was inside, the other arm swung into action. That arm of the antibody had been engineered to grab and block a protein called Beta-secretase, or bace1, which helps produce the plaques implicated in Alzheimer’s disease.
Biomedical engineer Elisa Konofagou at Columbia University is pursuing another way to sneak drugs into the brain, by drilling microscopic channels with a high-intensity ultrasound device similar to the therapeutic ultrasound doctors use to dislodge kidney stones. When pointed at the brains of mice, such vibrations might loosen the seals between the cells of the blood vessels inside, she suspected. Drugs could then pass through the barrier.
To boost the strength of the ultrasound, Konofagou injected the mice with a saline solution loaded with microscopic gas bubbles. (Previous research by other scientists had shown that ultrasound makes the bubbles resonate thousands of times a millisecond.) Rather than try to open up the blood-brain barrier throughout the brain, Konofagou and her colleagues focused a beam to zap a small patch. As they had hoped, a narrow ultrasound beam loosened the blood vessel walls in part of a mouse’s brain. Drugs circulating through the mouse’s blood were then able to slip through at that location. After the ultrasound treatment was finished, the blood-brain barrier closed back up.
Those experiments on mice left open a number of questions about whether the ultrasound method would work on humans, too. People have much thicker skulls than mice do, for one thing, so it might be necessary to use stronger sound waves to reach the blood-brain barrier inside. But really strong waves might end up cooking the brain’s tissue instead of judiciously loosening a blood vessel wall.
Recently Konofagou and her colleagues got closer to an answer by trying out their ultrasound technique on five monkeys. In July they reported that the ultrasound was able to pass through the monkeys’ skulls and almost instantly loosen small sections of the animals’ blood-brain barrier. The scientists kept careful tabs on the monkeys to see if the procedure did any lasting damage. They found that the leaks in the blood-brain barrier closed up in a matter of hours. Afterward, the test monkeys showed no signs of trouble in their behavior. They could move their arms and legs normally, they could still pass vision tests, and they slept well.
Nevertheless, ultrasound therapy and Trojan Horse molecules will not be showing up in doctors’ offices anytime soon. Both approaches still require a great deal of research before they are judged safe and effective for human use. The research is also expensive, and it has attracted only limited funding because it veers so far from conventional therapies.
But with the blood-brain barrier blocking so many potential drug therapies, somebody will figure out a practical way to tear down the wall. Poking holes in that fortress and forging portals of entry are prerequisites for treating many of the brain’s most intransigent and devastating ills.