One of the most important safeguards in our bodies is the blood-brain barrier (BBB). Created by tightly interlocked vessel wall cells, the barrier prevents viruses and other microscopic malcontents that could do much harm to our central nervous system from entering our central nervous system.

While the BBB is exceptional at keeping us safe, it poses a problem for people with diseases of the brain: it bars many therapeutics from getting to the places in the brain where they can be most effective.

Dr. Agessandro Abrahao is one of a multi-disciplinary team at Sunnybrook Research Institute that has been grappling with this problem for years.

Thanks to an ALS Canada-Brain Canada Discovery Grant, the team is closer than ever to solving the problem of the BBB using sophisticated, non-invasive technology that has the potential to revolutionize drug delivery for ALS.

Opening the blood-brain barrier

Dr. Abrahao, a neurologist, joined Sunnybrook in 2015 as a fellow under the supervision of his mentor, Dr. Lorne Zinman, the Sunnybrook ALS Clinic director. They began working with Dr. Kullervo Hynynen, Sunnybrook’s vice-president of research and innovation, who had discovered something extraordinary. Using focused ultrasound, you can use sound waves to create “micro-gaps,” like small windows, in the BBB. These gaps remain open for about 24 hours, during which drugs delivered to the bloodstream can “leak” into a target area.

Drs. Abrahao and Zinman wondered: could the focused ultrasound method be applied to the motor cortex? If so, drugs for diseases like ALS could potentially be delivered directly to the areas damaged by the disease, greatly increasing their effectiveness.

Dr. Hynynen’s answer was encouraging: they’d already successfully tested it in animals. It was time to see if it worked in humans.

“Let’s make history”

In 2018, a small cohort of people with ALS volunteered to undergo the procedure for a safety trial, funded by a previous ALS Canada Project Grant. They put on a helmet outfitted with up to a thousand small ultrasound elements in it. Then, using an MRI, the medical team directed the sound waves to the affected area of the brain with surgical precision.

Before the procedure began, the first participant in the trial said, “Let’s make history.”

And they did: the study successfully proved it was possible to safely breach the BBB in the motor cortex.

“The beauty of this technology is that we’re not doing an invasive, open surgery,” said Dr. Abrahao. “We’re using acoustic energy to puncture these small blood vessels and allow the medications to leak to specific regions of the brain. Then, they close up all on their own.”

A trial paved with gold

After this encouraging victory, Drs. Abrahao, Zinman, and Hynynen, Sunnybrook neurosurgeon Dr. Lipsman, and the team – which includes other ALS experts, neurologists, physicists, neurosurgeons, radiologists, and engineers – are now using funding from their latest Discovery Grant to run a Phase 2 clinical trial. Similar to the first trial, it will test using MRI-guided focused ultrasound to create microgaps in the BBB. But this time, there’s an added element (literally): gold.

The trial is partnering with a pharmaceutical company to test the delivery of gold nanoparticles to the brain in people with ALS. Research suggests that gold may be able to improve the metabolism in motor neurons that are degenerating in the brain, helping those cells survive longer. These gold nanoparticles are also currently being tested in ALS as an oral drug in the HEALEY Platform Trial.

This Phase 2 trial will further confirm the safety of the procedure, as well as its efficacy for delivering an actual therapeutic to motor neurons.

Dr. David Taylor, Vice President of Research for the ALS Society of Canada, is optimistic about the potential impact on drug delivery in ALS. “ALS is a disease of both upper and lower motor neurons and most experimental treatment delivery in clinical trial is focused more heavily on accessing the lower motor neurons of the spinal cord. By non-invasively targeting the motor cortex, MRI-guided focused ultrasound, if successful here, could open up avenues not only for new therapies, but also to enhance the efficacy of currently tested treatments in ALS. That prospect is very exciting.”

Brain Canada Chief Research and Programs Officer, Dr. Catherine Ferland agrees. “The potential is very exciting as it has implications for therapies that extend beyond ALS. The impact of this study will be significant for other neurological diseases where the BBB prevents drug entry, and it will inspire solutions that can make a big difference in the research landscape.”

Funding that makes an impact

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $24 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease. In 2022, nine projects awarded through the 2021 Discovery Grant Program will benefit from $1.125 million in funding.

The Discovery Grant Program has been made possible with the financial support of Health Canada, through the Canada Brain Research Fund, an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada, and of the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.

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Posted in: Research