Any self-cure for Alzheimer's disease and other brain disorders faced a major obstacle: the blood-barrier brain. This nearly impenetrable lining in brain capillary keeps viruses and other nasties, it also denies entry to many potential drugs and other treatments. Now researchers have developed a way to trick one of the guardians of this cellular defense system in escorting a potentially beneficial antibodies in the brain. They say their method can reduce amyloid-β levels, the main suspect in Alzheimer's disease, up to 50% in the brains of mice.
The new strategy is 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, said Ryan Watts, a neurobiologist at the biotech company Genentech in South San Francisco, California, and a leader of the new research. This is partly because these drugs also interfere with other enzymes and cause side effects. A better strategy, Watts and his colleagues reasoned, could be targeted with BACE1 antibodies, snipers of the immune system that can be designed to attack very specific molecular targets. There is one big problem with this idea, though :. Antibodies are too large to cross the blood-brain barrier
To overcome this obstacle, the Genentech team attempted a first strategy proven there about 20 years. He took advantage of the specific mechanism of the brain to get a necessary nutrient, iron, through the wall of endothelial cells that form the blood-brain barrier. Iron in the bloodstream is associated with a larger molecule called transferrin. Endothelial cells have a transferrin receptor which acts as a gatekeeper When transferrin binds to a receptor on the blood side of the barrier, the endothelial cell conveys (and its cargo of iron) to the other side and spits in the brain.
Scientific Genentech led by Mark Dennis designed an antibody with two arms, one that binds to BACE1 and inhibits its activity and which binds to endothelial cells of the transferrin receptor and tips in the transport antibody across the blood-brain barrier fence.
in a pair of papers published online today in Science Translational Medicine (see here and here), the researchers report that this approach greatly increases the effectiveness of the antibody . Without the linker to transferrin, only a small amount of BACE1 antibody entered the brain when the researchers injected intravenously in mice. About 10 times more than the version with the connecting arm to transferrin obtained in the brain, said Watts. More importantly, the reduced levels of antibody treatment of amyloid-β by up to half.
"Conceptually, it is a fascinating approach," said Todd Golde, Alzheimer's researcher at the University of Florida, Gainesville. The researchers have largely ignored the antibody-based therapies for brain disorders because it was not possible to obtain antibodies into the brain in concentrations high enough to be therapeutic, Golde said. the new study shows a possible solution, and which could in principle be adapted to other disorders the brain, he said.
William Pardridge, a researcher at the University of California, Los Angeles, who has long criticized the biotechnology and pharmaceutical companies not to develop strategies for therapies through blood-brain barrier, says Genentech may be the first large company to do so. "that someone Genentech think you need to solve the blood-brain barrier to deliver neurotherapeutics problem, which is an amazing advance."
However, both Pardridge and Golde are cool on the potential for the treatment of Alzheimer's disease with the specific antibody. They both point out that because only BACE1 antibody inhibits production new amyloid-β, it is not clear that it would help people whose brain is already riddled with clusters of amyloid plaquelike that characterize Alzheimer ' Alzheimer. Golde noted that most Alzheimer's researchers now believe the best chance of success for any therapy will begin treatment as soon as possible in the course of the disease, before significant deterioration occurred. According to him, it remains to be seen whether the new antibody therapy would be sufficiently safe and profitable for such long-term use in humans.
Watts accepts that there is more work to do, but he argues that these obstacles can be overcome. For example, he said, because humans and mice metabolic rate, lower doses may have similar beneficial effects in humans. "We are actively pursuing this," he said.
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