2024-01-16 19:47:04
A patient is receiving targeted ultrasound to help remove part of the blood-brain barrier and increase the effectiveness of the drug Aduhelm to treat Alzheimer’s at the Rockefeller Neuroscience Institute at West Virginia University. (Rockefeller Neuroscience Institute at West Virginia University via The New York Times)
We have a problem with the recently approved drug to treat Alzheimer’s, Aduhelm. Although it can eliminate part of the amyloid that makes up the brain plaques characteristic of this disease, most of the drug is wasted because it runs into an obstacle: the blood-brain barrier, which protects the brain from toxins and infections, but also prevents that many medications enter.
The researchers wondered if they might improve the disappointing result if they tried something different: opening the blood-brain barrier for a short time while administering the drug. Their experimental method was to use well-directed ultrasound pulses along with tiny gas bubbles to open the barrier without destroying it.
Researchers at the Rockefeller Neuroscience Institute at West Virginia University reported their results recently in The New England Journal of Medicine. When the barrier was opened, 32 percent or more of the plaque dissolved, said Ali Rezai, a neurosurgeon at the institute who led the study. The group did not measure the amount of antibodies entering (which would require labeling the drug with radioactivity), but in animal studies, opening the barrier allowed five to eight times more antibodies to enter the brain, Rezai said.
In its early stages, the experiment, which was only carried out with three patients with mild Alzheimer’s, was funded by this university and the Harry T. Mangurian, Jr. Foundation.
This was a preliminary safety study—the first stage of research—and was not designed to measure clinical outcomes.
But when the results were presented at a recent meeting, “our jaws dropped,” said Michael Weiner, an Alzheimer’s disease researcher at the University of California, San Francisco, who was not involved in the study.
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Doctors monitor a patient’s ultrasound method to help remove a portion of the blood-brain barrier and increase the effectiveness of the drug Aduhelm in treating Alzheimer’s, at West Virginia University’s Rockefeller Neuroscience Institute. (Rockefeller Neuroscience Institute at West Virginia University via The New York Times)
The researchers noted that it was an innovative, but complex, approach to a problem that Walter Koroshetz, director of the National Institute of Neurological Disorders and Stroke, considered one of the brain diseases whose treatment has a great challenge: how are drugs introduced into the brain?
Some antibodies, such as the Alzheimer’s drug aducanumab, which the company Biogen sells as Aduhelm, are excessively expensive; Its selling price is $28,000 for one year’s treatment. According to Koroshetz, one of the reasons for this high price is that only one percent of the antibodies injected into the bloodstream manage to cross the blood-brain barrier.
However, it took more than a decade to find a safe way to open that barrier. Researchers knew how the barrier worked, but because of its role in protecting the brain, opening it without damaging it meant keeping it open only for a very short time. It is a very delicate part of the circulatory system and not what many people imagine from its name.
“A lot of people think of it as something that wraps around the head,” a kind of turban for the brain, said Alexandra Golby, a professor of neurosurgery and radiology at Harvard Medical School.
Instead, the barrier is found at the end of many important blood vessels that supply the brain. When they reach the head, the vessels branch and divide until their ends form into narrow capillaries with extremely tight walls. This barrier does not allow large molecules to pass, but allows small molecules, such as glucose and oxygen, to pass.
The challenge was to open those walls without breaking the capillaries.
The solution turned out to have two elements. First, patients are injected with tiny microbubbles of perfluorocarbon gas. The bubbles range in size from 1.1 to 3.3 microns (a micron measures one-thousandth of a millimeter). Low-frequency ultrasound pulses are then directed to the area of the brain to be treated. The ultrasound pulses create waves in the fluid of the blood vessels so the microbubbles expand and contract with the waves rapidly. This opens the vessels without damaging them and gives access to the brain.
According to Golby, microbubbles are routinely used in ultrasound imaging studies of the heart and liver because they light up and reveal blood flow. Both the kidney and the liver filter them out of the body.
“We’ve used them safely for 20 years,” Golby said.
For the experiment described in this new paper, the researchers used ultrasound on one side of the brain, but not the other, and then performed scans of the brain to verify the results.
Although the targeted ultrasound method was successful as an experiment, not everything was so promising. The device was designed to deliver ultrasound to a small, specific area, but in cases of Alzheimer’s, the plaque containing amyloid is throughout the brain.
“If we want to get the amyloid out of the brain, we have to go in with a paintbrush and not a pencil,” he told Koroshetz.
Researchers intentionally target areas of the brain related to memory and reasoning, but it is not yet known whether the treatment improves outcomes. A larger study will be needed to find out.
The Alzheimer’s study is just one of many that involve opening the barrier to giving medications to patients with a wide variety of brain diseases.
It’s all in the early stages and so far everything shows that this method works; the drugs that mightn’t enter, now manage to do so.
A group led by Nir Lipsman, a neurosurgeon at the University of Toronto’s Sunnybrook Research Institute, and his colleagues opened the door to delivering a chemotherapy drug to the brains of four patients with breast cancer that had spread to the brain. The researchers reported that the concentration of the drug, trastuzumab, increased fourfold.
That work was funded by the Focused Ultrasound Foundation and sponsored by Insightec, which manufactures the ultrasound machine used.
Lipsman and his colleagues have already treated seven breast cancer patients and are expanding the study. They are also conducting preliminary studies on a wide variety of brain diseases, including cancer, Parkinson’s, and Lou Gehrig’s disease, or amyotrophic lateral sclerosis.
Golby and his colleagues have used this approach to treat patients with glioblastoma, a deadly type of brain cancer.
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