Ultrasound experiment tackles giant problem in brain medicine

Ultrasound experiment tackles giant problem in brain medicine

There is a problem with the recently approved Alzheimer’s drug, Aduhelm. It can remove some of the amyloid that forms the brain plaques characteristic of the disease. But most of the medicine is wasted because it hits an obstacle, the blood-brain barrier, which protects the brain from toxins and infections but also prevents many drugs from entering it.

The researchers wondered if they could improve this dismal outcome by trying something different: They would open the blood-brain barrier for a short time while they administered the drug. Their experimental method involved using highly focused ultrasonic pulses along with tiny gas bubbles to open the barrier without destroying it.

Investigators from the Rockefeller Neuroscience Institute at West Virginia University, reported their results last week in the New England Journal of Medicine. When the barrier was opened, 32 percent more plaque was dissolved, said Dr. Ali Rezai, a neurosurgeon at the institute, who led the study. The group did not measure the amount of antibodies penetrating – this would require radioactive labeling of the drug – but in animal studies, opening the barrier allowed 5 to 8 times more antibodies to enter. penetrate the brain, Dr. Rezai said.

The early-stage experiment, which was attempted on only three patients with mild Alzheimer’s disease, was funded by the university and the Harry T. Mangurian, Jr. Foundation.

This was a preliminary safety study – the first stage of research – and not designed to measure clinical outcomes.

But when the results were presented at a recent meeting, “our mouths dropped open,” said Dr. Michael Weiner, an Alzheimer’s disease researcher at the University of California, San Francisco, who not participated in the study.

The researchers said it was an innovative but challenging approach to a problem that Dr. Walter Koroshetz had proposed., director of the National Institute of Neurological Disorders and Strokes, considered one of the most difficult to treat in the treatment of brain diseases: how to get drugs into the brain?

Antibodies like the Alzheimer’s drug aducanumab, which the company Biogen sells under the name Aduhelm, are extremely expensive; Aduhelm’s sticker price is $28,000 per year. One reason for the high price, Dr. Koroshetz said, is that only 1 percent of the antibodies injected into the bloodstream cross the blood-brain barrier.

However, it took more than a decade to find a safe way to open this barrier. Investigators understood how the barrier worked, but opening it without causing damage meant keeping it open for a short time, due to its role in protecting the brain. This is a fragile part of the circulatory system and is not what many people imagine from the name.

“A lot of people think of it as something wrapped around the head,” like a turban for the brain, said Dr. Alexandra Golby, a professor of neurosurgery and radiology at Harvard Medical School.

Instead, the barrier is found at the ends of several major blood vessels that supply blood to the brain. As they enter the head, the vessels branch and divide until they form, at their ends, narrow capillaries with extremely tight walls. This barrier prevents large molecules from entering and allows small molecules like glucose and oxygen to enter.

The challenge was to open these walls without tearing the capillaries.

The solution turned out to have two elements. First, patients are injected with tiny microbubbles of perfluorocarbon gas. The bubbles extend into size 1.1 to 3.3 microns (one micron is approximately 0.000039 inch). Then, low-frequency ultrasound pulses are focused on the area of ​​the brain to be treated. Ultrasound pulses create waves in the fluid in blood vessels; microbubbles expand and contract quickly with waves. This opens the vessels without damaging them, allowing entry into the brain.

Microbubbles, Dr. Golby said, are commonly used in ultrasound imaging studies of the heart and liver because they light up, revealing blood flow. They are filtered out of the body by the kidneys and liver.

“They have twenty years of experience in security,” she said.

For the experiment described in the new paper, the researchers used ultrasound on one side of the brain but not the other, for comparison, then took brain scans to verify the results.

Although the focused ultrasound approach proved successful as an experiment, all was not rosy. The device was designed to deliver ultrasound to a small targeted area, but in cases of Alzheimer’s disease, amyloid-containing plaque is present throughout the brain.

“If you want to remove amyloid from the brain, you have to go with a paintbrush, not a pencil,” Dr. Koroshetz said.

The researchers deliberately targeted brain areas involved in memory and reasoning, but it remains to be seen whether the treatment improves outcomes. This will require a larger study.

The Alzheimer’s study is just one of many that aim to open the barrier to delivering drugs to patients with various brain diseases.

All are in their early stages and all, so far, show that the method works; blocked medications enter.

A group, led by Dr. Nir Lipsman, a neurosurgeon at the University of Toronto’s Sunnybrook Research Institute and colleagues, opened the barrier to deliver a chemotherapy drug to the brains of four breast cancer patients whose cancer had spread to his brain. The concentration of the drug, trastuzumab, increased fourfold. reported.

This work was funded by the Focused Ultrasound Foundation and sponsored by Insightec, which manufactures the ultrasound device used.

Dr. Lipsman and colleagues have now treated seven breast cancer patients and are expanding the study. They are also conducting preliminary studies on various brain diseases, including cancer, Parkinson, And ALS.

Dr. Golby, of Harvard Medical School, and his colleagues used this method to treat patients with glioblastoma, a deadly brain cancer.

One of the few chemotherapy drugs that can enter the brain is temozolomide. But even this is largely blocked; only 20 percent cross the blood-brain barrier.

So Dr. Golby’s Medical Center, Brigham and Women’s Hospital and several others got permission from the Food and Drug Administration to conduct a clinical trial, using focused ultrasound with microbubbles to deliver more chemotherapy. It was funded by Insightec.

The patients did well, but the aim of the study, which has not yet been published, was to assess the safety of the technique and not its effectiveness, she explained.

“I would like to see a trial of a drug that doesn’t normally enter the brain,” Dr. Golby said. There are many drugs that look great in laboratory studies but, she says, “completely fail” because they are blocked by the blood-brain barrier.

For now, however, questions remain – for example, where to target therapies in the brain.

But, said Dr. Jon Stoessl, a Parkinson’s disease specialist and professor of neurology at the University of British Columbia, the method “eliminates the problem that has always been a problem for anyone dealing with central nervous system disorders “.

Kullervo Hynynen, vice-president of research and innovation at Sunnybrook Research Institute in Toronto, is hopeful.

“If it works and is safe, it will open the door to a whole new way of treating the brain,” he said.

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Eric D. Eilerman

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