Biotechnology and health

The innovation that gets an Alzheimer’s drug

through the blood-brain barrier
Focused ultrasound is just one strategy researchers are using to get drugs
into the brain.

By Cassandra Willyard

January 12th, 2024

This 3-D illustration shows how ultrasound waves from inside the helmet converge on a focal point on the brain
used for blood-brain barrier opening.

WVU ROCKEFELLER NEUROSCIENCE INSTITUTE

This article first appeared in The Checkup, MIT Technology Review’s weekly
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Therapies to treat brain diseases share a common problem: they struggle to
reach their target. The blood vessels that permeate the brain have a special
lining so tightly packed with cells that only very tiny molecules can pass
through. This blood-brain barrier “acts as a seal,” protecting the brain from
toxins or other harmful substances, says Anne Eichmann, a molecular biologist
at Yale. But it also keeps most medicines out. Researchers have been working
on methods to sneak drugs past the blood-brain barrier for decades. And their
hard work is finally beginning to pay off.

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Last week, researchers at the West Virginia University Rockefeller

Neuroscience Institute reported that by using focused ultrasound to open the
blood-brain barrier, they

improved delivery of a new Alzheimer’s treatment and sped up clearance of the

sticky plaques that are thought to contribute to some of the cognitive and
memory problems in people with Alzheimer’s by 32%.

For this issue of The Checkup, we’ll explore some of the ways scientists are
trying to disrupt the blood-brain barrier.
An Alzheimer’s patient undergoes focused ultrasound treatment with the WVU RNI team.

WVU ROCKEFELLER NEUROSCIENCE INSTITUTE

In the West Virginia study, three people with mild Alzheimer’s received
monthly doses of aducanumab, a lab-made antibody that is delivered via IV.
This drug, first approved in 2021, helps clear away beta-amyloid, a protein
fragment that clumps up in the brains of people with Alzheimer’s disease. (The
drug’s approval was controversial, and it’s still not clear whether it actually
slows progression of the disease.) After the infusion, the researchers treated
specific regions of the patients’ brains with focused ultrasound, but just on one
side. That allowed them to use the other half of the brain as a control. PET scans
revealed a greater reduction in amyloid plaques in the ultrasound-treated
regions than in those same regions on the untreated side of the brain,
suggesting that more of the antibody was getting into the brain on the treated
side.

Aducanumab does clear plaques without ultrasound, but it takes a long time,
perhaps in part because the antibody has trouble entering the brain. “Instead of
using the therapy intravenously for 18 to 24 months to see the plaque reduction,
we want to see if we can achieve that reduction in a few months,” says Ali Rezai,
a neurosurgeon at West Virginia University Rockefeller Neuroscience Institute
and an author of the new study. Cutting the amount of time needed to clear
these plaques might help slow the memory loss and cognitive problems that
define the disease.

The device used to target and deliver the ultrasound waves, developed by a
company called Insightec, consists of an MRI machine and a helmet studded
with ultrasound transducers. It’s FDA approved, but for an entirely different
purpose: to help stop tremors in people with Parkinson’s by creating lesions in
the brain. To open the blood-brain barrier, “we inject individuals intravenously
with microbubbles,” Rezai says. These tiny gas bubbles, commonly used as a
contrast agent, travel through the bloodstream. Using the MRI, the researchers
can aim the ultrasound waves at very specific parts of the brain “with millimeter
precision,” Rezai says. When the waves hit the microbubbles, the bubbles begin
to expand and contract, physically pushing apart the tightly packed cells that
line the brain’s capillaries. “This temporary opening can last up to 48 hours,
which means that during those 48 hours, you can have increased penetration
into the brain of therapeutics,” he says.

Focused ultrasound has been explored as a method for opening the blood-
brain barrier for years. (We wrote about this technology way back in 2006.)
But this is the first time it has been combined with an Alzheimer’s therapy and
tested in humans.

The proof-of-concept study was too small to look at efficacy, but Rezai and his
team are planning to continue their work. The next step is to repeat the study in
five people with one of the newer anti-amyloid antibodies, lecanemab. Not only
does that drug clear plaque, but one study showed that it slowed disease
progression by about 30% after 18 months of treatment in patients with early
Alzheimer’s symptoms. That’s a modest amount, but a major success in a field
that has struggled with repeated failures.

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Eichmann, who is also working on disrupting the blood-brain barrier, says the
new results using focused ultrasound are exciting. But she wonders about long-
term effects of the technique. “I guess it remains to be seen whether over time,
upon repeated use, this would be damaging to the blood-brain barrier,” she says.

Other strategies for opening the blood-brain barrier look promising too.
Rather than mechanically pushing the barrier apart, Roche, a pharmaceutical
company, has developed a technology called “Brainshuttle” that ferries drugs
across it by binding to receptors on the cells that line the vessel walls.

The company has linked Brainshuttle to its own anti-amyloid antibody,

gantenerumab, and is testing it in 44 people with Alzheimer’s. At a conference
in October, researchers presented initial results. The highest dose completely
wiped out plaque in three of four participants. The biotech company Denali
Therapeutics is working on a similar strategy to tackle Parkinson’s and other
neurodegenerative diseases..

Eichmann is working on a different strategy. Her team is testing an antibody

that binds to a receptor that is important for maintaining the integrity of the
blood-brain barrier. By blocking that receptor, they can temporarily loosen the
junctions between cells, at least in lab mice.

Other groups are targeting different receptors, exploring various viral vectors,
or developing nanoparticles that can slip into the brain.

All these strategies will have different advantages and drawbacks, and it
isn’t yet clear which will be safest and most effective. But Eichmann thinks
some strategy is likely to be approved in the coming years: “We are indeed
getting close.”

Techniques to open the blood-brain barrier could be useful in a whole host of

diseases—Alzheimer’s, but also Parkinson’s disease, ALS, and brain tumors.
“This really opens up a whole array of potential opportunities,” Rezai says. “It’s
an exciting time.”

Read more from MIT Technology Review’s archive

Until recently, drug development in Alzheimer’s had been a dismal pursuit,
marked by repeated failures. In 2017, Emily Mullin looked at how failures of
some of the anti-amyloid drugs had researchers questioning whether amyloid is
really the problem in Alzheimer’s.

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In 2016, Ryan Cross covered one of the first efforts to use ultrasound to open
the blood-brain barrier in humans, a trial to deliver chemotherapy to patients
with recurrent brain tumors. That same year, Antonio Regalado reported some
of the first exciting results of the Alzheimer’s drug aducanumab.

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