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Thursday, May 26, 2011

Tricking the Brain Into Taking Its Medicine

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Green light. Antibodies that bind to the transferrin receptor (green) can cross the blood-brain barrier and potentially help deliver therapies to neurons (red).
Credit: Yu et al., Science Translational Medicine
Any would-be cure for Alzheimer’s disease or other brain disorder faces a daunting obstacle: the blood-brain barrier. This nearly impenetrable lining in the capillaries of the brain keeps out viruses and other bad guys, but it also denies entry to many potential drugs and other treatments. Now researchers have devised a way to trick one of the gatekeepers in this cellular defense system into escorting a potentially beneficial antibody into the brain. They report that their method can reduce levels of amyloid-β, the prime suspect in Alzheimer’s disease, by up to 50% in the brains of mice.
The new strategy targets an enzyme that helps produce amyloid-β. Efforts to inhibit this enzyme, called β-secretase 1 (BACE1), with small molecule drugs have met with limited success so far, says Ryan Watts, a neurobiologist at the biotech company Genentech in South San Francisco, California, and one of the leaders of the new research. That’s partly because these drugs also interfere with other enzymes and cause side effects. A better strategy, Watts and colleagues reasoned, might be to target BACE1 with antibodies, immune system sharpshooters that can be designed to attack very specific molecular targets. There’s a big problem with that idea, though: antibodies are too big to cross the blood-brain barrier.
To overcome that obstacle, the Genentech team tried a strategy first demonstrated about 20 years ago. It took advantage of the brain’s own mechanism for getting a necessary nutrient, iron, across the lining of endothelial cells that form the blood-brain barrier. Iron in the bloodstream is bound to a bulky molecule called transferrin. The endothelial cells have a receptor for transferrin that acts like a gatekeeper: When transferrin binds to a receptor on the blood side of the barrier, the endothelial cell transports it (and its iron cargo) to the other side and spits it out into the brain.
Genentech scientists led by Mark Dennis designed an antibody with two arms—one that binds to BACE1 and inhibits its activity and one that binds to the transferrin receptor and tricks endothelial cells into transporting the antibody across the blood-brain barrier.
In a pair of papers published online today in Science Translational Medicine (see here and here), the researchers report that this approach dramatically increased the effectiveness of the antibody. Without the transferrin-binding arm, only a small amount of the BACE1 antibody got into the brain when the researchers injected it intravenously in mice. About 10 times as much of the version with the transferrin-binding arm got into the brain, Watts says. More important, the antibody treatment reduced levels of amyloid-β by up to half.
“Conceptually, it’s a fascinating approach,” says Todd Golde, an Alzheimer’s researcher at the University of Florida, Gainesville. Researchers have largely ignored antibody-based treatments for brain disorders because it hasn’t been possible to get antibodies into the brain in high enough concentrations to have a therapeutic effect, Golde says. The new study shows a possible solution, and one that could in principle be adapted for other brain disorders, he says.
William Pardridge, a researcher at the University of California, Los Angeles, who has long criticized biotech and pharmaceutical companies for not developing strategies to get therapies across the blood-brain barrier, says Genentech may be the first major company to do so. “That someone at Genentech thinks you need to solve the blood-brain barrier problem to deliver neurotherapeutics, that is a stunning advance.”
However, both Pardridge and Golde are lukewarm on the potential for treating Alzheimer’s disease with this specific antibody. They both point out that because the BACE1 antibody only inhibits new amyloid-β production, it’s not clear that it would help people whose brains are already riddled with the plaquelike clusters of amyloid that characterize Alzheimer’s disease. Golde notes that most Alzheimer’s researchers now think the best chance of success for any therapy will be to begin treatment as early as possible in the course of the disease, before significant degeneration has occurred. He says it remains to be seen whether the new antibody therapy would be sufficiently safe and cost-effective for such long-term use in humans.
Watts agrees that there’s more work to be done, but he argues that these obstacles may be surmountable. For example, he says, because humans and mice have different metabolic rates, lower doses may have similar beneficial effects in humans. “We are aggressively pursuing this,” he says.

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