Friday, May 24

An ultrasound experiment tackles a giant problem in brain medicine

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

The researchers wondered whether they could improve that dismal outcome by trying something different: They would open the blood-brain barrier for a short time while administering the drug. Their experimental method was to use pulses of highly focused ultrasound along with tiny gas bubbles to open the barrier without destroying it.

Researchers at West Virginia University’s Rockefeller Neuroscience Institute reported their findings 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 team didn’t measure how much antibodies entered — which would require radiolabeling the drug — but in animal studies, opening the barrier allowed 5 to 8 times more antibodies to enter the brain, he said. said Dr. Rezai.

The early-stage trial, which was tried in only three patients with mild Alzheimer’s, was funded by the university and the Harry T. Mangurian, Jr. Foundation.

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

But when the findings were presented at a recent meeting, “our mouth dropped,” said Dr. Michael Weiner, an Alzheimer’s researcher at the University of California at San Francisco who was not involved in the study.

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

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

However, finding a safe way to open that barrier took more than a decade. Investigators understood how the barrier worked, but opening it without causing damage meant keeping it open only for a short time, given its role in protecting the brain. It is a fragile part of the circulatory system and is not what many people imagine, based on its name.

“A lot of people think of it as something that gets 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 the brain. When they enter the head, the vessels branch and divide until they form, at their ends, narrow capillaries with extremely narrow walls. This barrier keeps large molecules out and allows small molecules such as glucose and oxygen to enter.

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

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

Microbubbles, Dr. Golby said, are routinely 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 20 years of security experience,” he 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 performed brain scans to verify the results.

Although the focused ultrasound approach proved to be a successful experiment, not all was rosy. The device was designed to deliver ultrasound to a small, targeted area, but in cases of Alzheimer’s, amyloid-containing plaques are found throughout the brain.

“If you want to remove amyloid from the brain, you need to do it with a brush, 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 will improve the results. This will require a larger study.

The Alzheimer’s study is one of many that involve opening the barrier to administer drugs to patients with a variety of brain diseases.

They are all in the early stages and all, so far, demonstrate that the method works; blocked drugs enter.

A team, led by Dr. Nir Lipsman, a neurosurgeon at the University of Toronto’s Sunnybrook Research Institute, and his colleagues, has broken the barrier to administering a chemotherapy drug to the brains of four breast cancer patients whose cancer had spread to the brain. The concentration of the drug, trastuzumab, quadrupled.

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

Dr. Lipsman and his colleagues have now treated seven breast cancer patients and are expanding the study. They are also conducting preliminary studies on a variety of brain diseases, including cancer, Parkinson’s disease and ALS

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

One of the few chemotherapy agents that can penetrate the brain is temozolomide. But even this is mostly blocked; only 20% pass the blood brain barrier.

So Dr. Golby’s medical center and several others got permission from the Food and Drug Administration to do a clinical trial, using focused ultrasound with microbubbles to deliver more chemotherapy. It was funded by Insightec.

The patients did well, but the purpose of the study, which has not yet been published, was to evaluate the safety of the technique, not its effectiveness, he said.

“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, he said, “totally fail,” because they are blocked by the blood-brain barrier.

For now, however, questions remain, such as where in the brain to target therapies.

But, said Dr. Jon Stoessl, a Parkinson’s expert and professor of neurology at the University of British Columbia, the method “eliminates the problem that has historically been a problem for anyone treating central nervous system disorders.”

Kullervo Hynynen, vice president for research and innovation at Sunnybrook Research Institute in Toronto, is confident.

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