Focused ultrasound and cautious optimism
Preclinical trials for the treatment of Alzheimer’s disease with focused ultrasound have also shown some encouraging results. To start with, simply opening the blood-brain barrier appears to have positive cognitive effects, such as improving memory function. Elisa Konofagou, a professor of biomedical engineering and radiology at Columbia University in New York, and other researchers found that remnants of amyloid beta plaque, one of the hallmarks of Alzheimer’s disease, are cleared from the brain when the barrier is open. No one knows exactly why, but it’s a start.
Other potential uses of focused ultrasound, such as gene therapyare not that close to the clinical trial stage, but the researchers hope that they will not have to wait too long.
At the Comprehensive Center for Neurosciences in Madrid, the neurologist and professor José Obeso and his research team have discovered that viral vectorswhich use harmless viruses as a gene delivery system, can cross the blood-brain barrier in non-human primates after focused ultrasound treatment and deliver the instructions to cure proteins that fight neurodegeneration such as Parkinson’s disease.
In theory, brain cells will absorb the genes and then make proteins that restore brain function or block unwanted activity in a certain brain region. The principle has been shown to work and is effective in rodents, but the unpublished results would be the first to show that this is also the case in monkeys. “If it works in monkeys, it most likely works in humans.”
There are currently no proven therapies to modify the course of brain diseases such as Parkinson’s, so “any hope of providing a treatment where there was none before is obviously something to consider,” says Jon Stoessl, a Parkinson’s researcher and head of neurology at the University of British Columbia, Canada, and editor-in-chief of the peer-reviewed medical journal Movement Disorders.
Still, Stoessl warns against giving premature hopes to the people. Focused ultrasound for neurodegenerative diseases is generally not as advanced as it is for cancer. With cancer, doctors have a much clearer understanding of where to administer drugs. That’s not the case for conditions like Parkinson’s and ALS, where researchers are still trying to figure out which parts of the brain are affected and how.
The expectations generated by this new method
For many experts and patients, however, approved focused ultrasound treatments may not come soon enough. Just consider the effects of Alzheimer’s disease and its related forms of dementia, which affect 57 million people worldwide, a number that is expected to triple by 2050. Hundreds of Alzheimer’s drugs have failed clinical trials at a cost of billions of dollars. Some researchers speculate that this is because they do not reach the brain in adequate concentrations. Providing high doses by conventional means would require potentially toxic doses. An obvious benefit of focused ultrasound is that because the dose is aimed at the brain, lower amounts would be effective.
While these apps address illnesses that tend to affect older people, there are others who would benefit from this new way of delivering medication. In Columbia, New York, Konofagou has been using this technology to treat pediatric patients with a terminal form of brain cancer called diffuse midline glioma. This type of brain tumor affects young children and is fatal within a year of diagnosis. The challenge for her has been to make this technology more accessible.
For the procedure Butler faces in Toronto, doctors designed the treatment to precisely deliver drugs to what remains of his tumor and its immediate surroundings without affecting nearby tissue. Before administering the therapy, Lipsman sat in an adjacent control room creating a high-resolution three-dimensional map of Butler’s brain and pinpointing where she wanted to open the blood-brain barrier to target her chemotherapy.
From there, the team followed a highly coordinated sequence of events. Butler took a chemotherapy pill 45 minutes into the procedure. When the chemotherapy reached peak concentration in his bloodstream, technicians injected microscopic gas-filled bubbles into his veins intravenously. These bubbles are smaller than red blood cells and pass harmlessly through the body while absorbing ultrasound energy.
For the next 90 seconds, Lipsman directed the focused ultrasound helmet to emit targeted energy to a precise location the size of an egg in Butler’s brain. The ultrasound waves activated the microbubbles to rapidly expand and contract, loosening the tight junctions of the blood-brain barrier and opening passageways for drug molecules to flow through and come into direct contact with the tumor, as well as its rim around the surrounding region.
“Scientifically and medically, the feat is revolutionary,” says Lipsman. But a lot of specialized equipment and trained personnel are needed and not all hospitals or clinics will have these resources.
Impatient with lack of funding, access to MRI, and technology partners, Konofagou developed a wearable neuronavigation system that does not rely on MRI to guide focused ultrasound to open the blood-brain barrier. By dispensing with a dedicated MRI machine, he came up with a simpler solution using existing MRI images to find the target and then opens the barrier with ultrasound waves from a handheld device. It doesn’t offer as precise control as magnetic resonance imaging (MRI)-guided systems, but it works.
Kullervo Hynynen, the University of Toronto medical physicist who pioneered the use of microbubbles and MRI-guided focused ultrasound, is also developing a customizable focused ultrasound helmet that can be used without the real-time guidance that an MRI machine provides when the patient is inside it.
The reusable helmet will reduce the cost of image guidance at an estimated $500 for the entire series of treatments, compared with the current cost of about $1,000 per session, he estimates. With more technological advances it will eventually be possible for patients to receive treatments in the comfort of their own homes. “That’s the long-term dream,” says Hynynen, who is also vice president of research and innovation at Sunnybrook. He believes Canadian government approval for the device itself is only five years away.
An opportunity worth taking
Given such expectations, several teams are already working to refine the technology involved in focused ultrasound. Insightec, a sponsor of the Sunnybrook Health Sciences Center in Canada, currently manufactures one of the most widely used MRI-guided focused ultrasound devices for opening the blood-brain barrier. Lipsman says the company is developing ways to make the treatment more more tolerable for patientsfor example, by eliminating the need to shave the head and put pins in the skull.
And when it comes to government approval, Lipsman believes cancer applications, such as primary or secondary brain cancers, have a good chance of moving forward in the next two to three years. This is because the desired outcomes, such as reduced tumor size or increased survival rates, are much simpler and require less time to define than those of neurodegenerative diseases. From there, he hopes that larger neurodegenerative disease trials will not be far behind.
In February, Michael Butler marked a year since his first prognosis, the minimum time he was expected to survive when he was diagnosed in 2021. The maximum term he was given, 18 months, will be in August. He is using every minute of that time. Following his last focused ultrasound treatment, in October 2021, he and his wife, Valerie, took an epic train ride through the Canadian Rockies to celebrate their 15th wedding anniversary, recently taking their children and grandchildren to Disney World.
In March 2022, after scans showed new tissue in the same chemotherapy-treated area of the original tumor, Butler immediately underwent another surgery. The lab results provided immense relief. It was just scar tissue and no more cancer.
Butler, a self-described dreamer, says he volunteered for these sometimes laborious — and certainly not guaranteed — clinical trials so he could have more time with his children and grandchildren. He did it too for Valerie and all the ski trips and Harley Davidson rides they have planned. “I’ll be a lab mouse,” he says, adding that he hopes there are more focused clinical trials of ultrasound that he can participate in. “I will take any chance I can.”