Potential drugs for neurodegenerative disorders such as multiple sclerosis (MS) and Alzheimer’s disease have been stymied by their inability to cross the blood brain barrier (BBB), a system of unique blood vessels that acts as a natural barricade between the brain and the rest of the body. This barrier, designed to block potentially harmful substances from reaching neural tissue, also holds back the very agents designed to target disease. But two new techniques, one using endogenous adenosine receptors and another using ultrasound, may offer doctors the ability to not only open the BBB but also control the length of time it remains open.
Better understanding of the BBB yields new targets
In the past decade, scientists learned more about the BBB’s make-up and how it works to protect the brain (see story, "Deeper understanding of the blood-brain barrier may lead to targeted treatments"), but Elena Batrakova, a researcher who studies BBB transport at the University of Nebraska Medical Center says it may yet have a few secrets.
“We know of four distinct features that make the BBB such a protective barrier. It is made up of tight junctions; it has special proteins along the membrane that catch different drugs and agents; it has a low rate of endocytosis [the process by which cells absorb outside molecules]; and the cells within the BBB have a high metabolism. These are very effective,” she says, “and there are likely other features that we just don’t know about yet.”
Researchers at the Cornell University College of Veterinary Medicine have taken an “if you can’t beat 'em, join 'em” approach by targeting adenosine receptors, small proteins that help to modulate BBB function. Margaret Bynoe, an MS researcher and one of the lead authors of a study published in the Sept. 14 Journal of Neuroscience, learned that adenosine not only played a role in regulating immune response in the disease but also in allowing molecules to pass through the BBB.
“Adenosine receptors are directly expressed on the BBB cells. They are an endogenous molecule produced by the body,” Bynoe says. “There are already drugs out there that can modify this receptor’s signaling, and we discovered that they also work on the BBB, to either open or tighten the barrier.”
Bynoe and colleagues used the FDA-approved drug Lexiscan to modify adenosine receptor behavior in mice. This not only opened the BBB but also allowed the transport of specific antibodies designed to remove amyloid beta, a protein implicated in Alzheimer’s disease.
“This is a process that is reversible, which is important for safety,” she says. “But the other important thing is that using adenosine receptors is time-dependent. You don’t want to leave the BBB open for a long time—it could be harmful to the brain. Using different drugs, we can allow it to stay open long enough to transport in the drugs but not so long that other things can make their way across, too.”
Relying on ultrasound
Biomedical engineers at Columbia University also have had success opening the BBB and inserting therapeutic agents—using quick pulses of ultrasound waves to disrupt the barrier’s normal function. A study led by Elisa Konofagou, an associate professor of biomedical engineering and radiology, was published in the Sept. 19 Proceedings of the National Academy of Sciences, demonstrated that not only could these short-pulse ultrasound waves open the BBB but they could limit the opening specifically to the hippocampus, an area of the brain decimated by Alzheimer’s disease.
“This is a focused ultrasound pulse—and at the focus itself, you can cause mechanical changes to the tissue and open it,” says Konofagou. “But more importantly, you can limit the focus to a very tiny region and do so non-invasively.”
To control the duration of the opening, Konofagou and her team used microbubbles, microscopic gas-filled bubbles that are commonly used as a contrast agent in ultrasound imaging. “How long the barrier is opened depends on the size of the microbubbles,” she says. “A one-micro microbubble will result in an opening that lasts between three hours and a day, whereas a four or six-micro bubble will cause a bigger opening that could take anywhere between two and five days to close.”
Konofagou argues the ultrasound technique, and limiting the BBB opening to a specific region of the brain, is not only safer for patients but more cost-effective. It allows doctors to get targeted (and very expensive) drugs to the areas of the brain most affected by the disease and avoids the side effects that may come from opening the barrier across the entire brain.
Both Bynoe and Konofagou say that there is still a long road before clinicians can successfully—and safely—open the BBB in human patients. Also, one approach may be more effective in treating certain diseases, while another technique may work better for others. Still, Konofagou has moved on to primate models and has strong preliminary data.
“Before this can move to clinical trials, we need to make sure that the behavior of the animal is not affected,” she says. “We haven’t seen any behavioral changes yet, but you have to be thorough.”
Batrakova, whose lab is looking to cross the barrier using the body’s natural inflammation response cells to cross the BBB, believes it is only a matter of time before scientists get there.
“The BBB is very, very good at what it does, [but] many of us are working on this problem,” she says. “And we will keep working until we get there.”