Sunnybrook neurobiologist Dr. Isabelle Aubert is working in the laboratory to develop therapies that may revolutionize the treatment of Alzheimer’s disease and other neurodegenerative disorders<strong>.</strong>
Never underestimate the sometimes serendipitous nature of scientific discovery.
Dr. Isabelle Aubert, a senior scientist and neurobiologist at Sunnybrook Research Institute in Toronto, certainly does not.
It was in 2007 that Dr. Aubert began studying whether combining antibodies and a revolutionary technology to open the blood-brain barrier, called focused ultrasound, could reduce the sticky, plaque-like clumps of amyloid peptides in the brain that are a hallmark of Alzheimer's disease. She and her collaborator Dr. Kullervo Hynynen, director of Physical Sciences, indeed found this to be the case in their experiments involving mice with characteristics of Alzheimer's disease.
But Dr. Aubert noticed something else: it appeared that mice in the study's control group, who had their blood-brain barrier opened but did not receive a dose of antibodies, were also benefitting.
"It looked like something was happening with focused ultrasound alone, which was a very exciting finding," says Dr. Aubert. As her investigation progressed, it became clear that simply opening the barrier reduced plaque and increased newborn cells in the hippocampus, a brain region involved in learning and memory.
Within seven years, she and Dr. Hynynen would go on to publish five world's-first findings from their lab-based Alzheimer's research.
It is transformational research like theirs that recently led the Focused Ultrasound Foundation to name Sunnybrook as one of only six Focused Ultrasound Centres of Excellence in the world – and the first in Canada.
Most Canadians are familiar with ultrasound in the context of medical imaging. The sound waves of ultrasound, however, can also treat disease.
With high-intensity focused ultrasound, MRI-guided beams of focused ultrasound harmlessly pass through bone and healthy tissue to destroy the target at their focal point, such as cancer cells or brain cells responsible for movement disorders like essential tremor.
'Focused ultrasound has extraordinary potential for disorders of the brain.'
Dr. Isabelle Aubert,
Senior Scientist
Sunnybrook Research Institute
Low-intensity focused ultrasound (LIFU) works on a similar basis, with important differences. LIFU can open the previously impenetrable blood-brain barrier, which lines the blood vessels in the brain to restrict the passage of toxic substances from the bloodstream into the brain.
The barrier also blocks medications and other helpful therapies; about 97 per cent of all molecules that could be tested for brain treatments cannot penetrate the barrier.
With LIFU, microscopic bubbles are first injected into the bloodstream and travel throughout the circulatory system. Once they reach the brain's blood vessels, they are targeted with beams of ultrasound, which cause the microbubbles to expand and contract. This loosens the tightly packed cells of the barrier, temporarily increasing its permeability and allowing drugs – also injected into the bloodstream – to reach the brain in a targeted way.
Using LIFU in 2015, Sunnybrook became the first in the world to non-invasively breach the blood-brain barrier and deliver chemotherapy into the brain tumour of a patient.
The potential of being able to safely and temporarily open the barrier, as Sunnybrook has done, is immense. It raises the possibility of transforming treatment of humanity's most challenging diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) and terminal brain tumours.
Sunnybrook will soon enrol patients in the world's first clinical trial to use focused ultrasound to open the blood-brain barriers of patients with Alzheimer's.
While the trial's primary objective is to prove the barrier can be safely and temporarily opened in people with Alzheimer's, it may also offer some evidence as to whether simply opening the barrier, without injecting antibodies or other therapeutics, can lead to reductions in amyloid plaques, as demonstrated in the cutting-edge laboratory research of Dr. Aubert and Dr. Hynynen.
Dr. Aubert hypothesizes that simply opening the barrier allows the body's own natural defenses, including blood-borne antibodies, to help clear amyloid. Antibodies are proteins that help the body's immune system to identify and eliminate disease.
Dr. Aubert is working hard to prepare for the day when Sunnybrook is ready to conduct a clinical trial with Alzheimer's patients that combines blood-brain barrier opening and targeted therapeutics.
She's investigating a variety of promising therapeutics, including antibodies, gene therapy that can prompt the brain to restore brain cell functioning, and stem cells that can improve brain function.
"Antibody therapy is the leading candidate for a future clinical trial, because several antibodies are already approved by regulators and some have the potential to be more effective when delivered past the barrier," says Dr. Aubert.
Adding blood-brain barrier opening to the mix could be a game-changer. Without opening it, high doses of antibodies are required just to get a limited number into the brains of Alzheimer's patients. In one of Dr. Aubert's preclinical studies, antibodies reduced amyloid plaque in just four days when the barrier was opened; this can take several weeks without opening.
"Focused ultrasound has extraordinary potential for disorders of the brain," says Dr. Aubert. Looking back, she remembers her initial reaction to the idea of opening the barrier with focused ultrasound.
"Dr. Hynynen described what he wanted to do, and I thought, 'This is so cool, but it also sounds so futuristic,'" Dr. Aubert says, recalling his arrival at Sunnybrook in 2006. "I was obviously very intrigued, so we discussed further and started collaborating right away."
A decade later, the future is now.
Beyond Alzheimer's
Through collaboration with other scientists, Dr. Isabelle Aubert's novel laboratory research extends beyond Alzheimer's disease to include other devastating neurodegenerative conditions, such as Parkinson's disease.
Their approach to Parkinson's is similar to the Alzheimer's approach: sneak therapeutics across the blood-brain barrier with the aid of focused ultrasound. Dr. Aubert and colleagues are testing whether it is possible to prevent neurodegeneration and improve functioning in the brains of mice with characteristics of Parkinson's disease by directing therapeutic genes past the barrier.
In another preclinical study, Dr. Aubert used focused ultrasound to deliver gene therapy across the blood-spinal cord barrier, a major impediment to treating spinal cord injury or disease.
To open the blood-brain barrier, MRI-guided beams of focused ultrasound target blood vessels in the brain with pinpoint precision. Microscopic bubbles – previously injected into the bloodstream – expand and contract when hit by the beams, loosening the tightly packed cells of the barrier. This temporarily increases the barrier's permeability and allows therapeutics – also injected into the bloodstream – to reach the brain in a targeted way.
Illustration: Hang Yu Lin / Aubert lab / Sunnybrook Research Institute
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