(Photograph by Kevin Van Paassen)
Amyotrophic lateral sclerosis, or ALS, is a devastating disease with a grim prognosis. By opening the blood-brain barrier with focused ultrasound, Sunnybrook researchers have made important progress toward new treatments and new hope.
In early 2014, Hanna Hadden noticed that something was wrong with her fingers.
The former teacher from Scarborough, Ont., was counting donations at her church. “I found I could not pick up coins,” she says.
It took several appointments with medical specialists over the next year and a half to discover what was affecting her dexterity. Hanna was in the early stages of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.
“I was shocked at the diagnosis,” Hanna recalls. “It’s not something I ever expected.”
ALS is a degenerative brain disease that causes gradual paralysis as the motor neurons stop communicating with muscles. As these nerve cells die, gradual paralysis sets in, affecting a person’s ability to walk, talk, eat, swallow and eventually breathe. Diagnosis typically occurs between the ages of 40 and 70, with an average age of 55 at the time of diagnosis.
About 3,000 people in Canada are living with ALS and 80 per cent die within two to five years after getting diagnosed. There is no cure.
“ALS is one of the worst diseases on the planet,” says neurologist Dr. Lorne Zinman, director of Sunnybrook’s ALS clinic and an associate scientist in the Hurvitz Brain Sciences Research Program. “It’s an awful neurological disease, and currently we can only mildly slow progression.”
NEW, EXPERIMENTAL TREATMENTS
Hanna, now 70 years old, started receiving care at Sunnybrook in 2015.
From her earliest appointments, she’d ask Dr. Zinman about the possibility of experimental treatments and clinical trials.
During one appointment, Dr. Zinman told Hanna about a revolutionary trial testing focused ultrasound to open the blood-brain barrier in people with ALS.
OPENING THE BLOOD-BRAIN BARRIER
The blood-brain barrier is a network of closely spaced cells that protects the brain by keeping out toxins, viruses and bacteria in the bloodstream, but it also prevents drug therapies from reaching the brain.
“The blood vessels in this area are so small, they act like a physical barrier,” says neuroscientist Dr. Nir Lipsman, director of the Harquail Centre for Neuromodulation at Sunnybrook and team member of this clinical trial. “We need to ‘open the gates.’”
By targeting and opening the blood-brain barrier in specific regions of the brain, Sunnybrook researchers can deliver promising medications directly and try to treat diseases such as ALS.
TARGETING THE BRAIN’S MOTOR CENTRE
While Sunnybrook researchers have made huge strides using focused ultrasound, successfully opening the blood-brain barrier in patients with brain tumours and Alzheimer’s disease, the idea of using focused ultrasound to treat ALS was a first.
Never before had anyone opened the blood-brain barrier over the motor cortex, the area of the brain responsible for controlling the body’s voluntary movements.
“We had to prove the feasibility of opening this region of the brain, and that it was safe and reversible in patients with ALS,” Dr. Zinman says.
His team would need to show that the blood-brain barrier would close again after temporarily being opened after the procedure.
In spring 2018, Sunnybrook began looking for volunteers with ALS to undergo this non-invasive procedure to open the blood-brain barrier over the motor cortex. Phase 1 of the clinical trial involved a small group of patients to determine the procedure’s efficacy and safety. Follow-up studies will add the delivery of a promising therapeutic for ALS.
How focused ultrasound (FUS) opens the blood-brain barrier
1. Focused ultrasound directs a thousand beams of energy at a low frequency to a specific area.
2. The sound waves vibrate microbubbles that have been injected into the bloodstream, causing them to expand and contract
3. The microbubbles gently push against the blood-brain barrier, causing it to open
VOLUNTEERING HER TIME
Hanna was one of the first to volunteer. She qualified for the trial because she was otherwise healthy and could tolerate being in a magnetic resonance imaging (MRI) machine for a prolonged period, which was a key part of the procedure. Also important was the fact that Hanna’s ALS had not yet impaired her breathing, as it often does with people in later stages of the disease.
“Because of my condition, I didn’t know what else I could do to help,” Hanna says of her decision to take part in the clinical trial. “I was quite enthusiastic, because it sounded quite innovative.”
“Patients with ALS are so altruistic and committed to finding treatments for this terminal disease.”
– Dr. Lorne Zinman,
Director, ALS Clinic at Sunnybrook
Hanna’s hands have been deeply affected by the disease. After breaking her ankle last spring and being in hospital and then rehab for weeks, she subsequently lost her ability to walk and now needs a wheelchair.
She has a personal support worker visit her home three times a day and needs two people to help her use her stair lift and get into cars. But despite these hurdles, Hanna was determined to participate in the clinical trial for the sake of furthering science.
“It may be the last good deed I can do to help other people with this disease,” she says.
HOPE ON THE HORIZON
And so one early morning last August, with her head freshly shaved for the procedure, Hanna headed to Sunnybrook. Hanna says she didn’t sleep the night before the big day, “Anytime you’re excited about something, you don’t sleep the night before anyway.”
Three other patients from the ALS clinic had already gone through the process that summer. Sunnybrook has the largest ALS clinic in Canada, with approximately 250 new patients diagnosed each year. Dr. Zinman says many of these people are eager to contribute to medical research.
“Patients with ALS are so altruistic and committed to finding treatments for this terminal disease,” he says. “They understand that although the research study may be in its earliest stages and may not benefit them individually, they accept the potential risks to help others.”
Hanna soon found herself being fitted with a special helmet lined with a thousand tiny ultrasound transducers, which convert electrical energy into sound energy. Then, she was placed into an MRI machine, so researchers could map out the motor cortex for precise targeting by the ultrasound waves.
That’s when doctors turned on the focused ultrasound inside the helmet. Thousands of low-frequency ultrasound waves converged on key points, hitting right near the blood-brain barrier of the motor cortex. “The frequency is so low, it’s harmless to the brain,” Dr. Lipsman says.
Tiny microbubbles are injected intravenously, and the ultrasound waves cause them to vibrate at the targeted brain regions. As they expand and contract, the microbubbles gently push against the sides of the tiny blood vessels around the motor cortex, eventually creating a small opening in the blood-brain barrier. Intravenous contrast is then injected to observe the blood-brain barrier opening on MRI.
After this four-hour procedure, Hanna stayed overnight in hospital to be closely monitored and had an MRI the next morning to determine if the blood-brain barrier had closed again. It had.
“The blood-brain barrier has an important function which needs to be restored. We want this therapeutic window to be opened only temporarily and then repair itself over a few hours,” says neurologist Dr. Agessandro Abrahao, a fellow at Sunnybrook with the ALS clinic who’s part of the research team.
“It’s been incredibly exciting for me to be involved in this world-class research. We are so pleased that this non-invasive procedure has been safe and well tolerated by all the trial participants,” Dr. Abrahao says.
The team at Sunnybrook is now moving ahead with plans to start Phase 2 of the trial. This study will include the use of a therapeutic agent and Drs. Abrahao, Zinman and Lipsman hope to begin in the fall.
Over time, researchers will likely develop therapies for ALS designed for this type of direct-to-the-brain use. Antibodies, gene or viral therapy, for instance, might be ideal.
Antibodies directed to specific targets can be used to decrease toxic proteins or reduce harmful inflammation. Gene therapy can involve replacing a mutated gene that causes disease with a healthy copy of the gene, or knocking out a mutated gene that is functioning improperly. Viral therapy can involve reprogramming viruses in the lab into therapeutic agents that can be used to kill harmful cells.
It is believed that these kinds of therapies could potentially improve, or even reverse, the damage caused by ALS, resulting in better motor function and a longer life span for people with the disease.
Being able to open up the blood-brain barrier around the motor cortex could also eventually lead to more effective treatments for other neurological diseases that impact movement, such as Parkinson’s disease and Huntington’s disease.
Once the process for opening the blood-brain barrier is refined and effective drugs are developed, Dr. Lipsman says it will be possible that focused ultrasound could be used in any hospital for ALS treatment.
“There are upfront costs for equipment,” he says. But because opening the blood-brain barrier helps medication get to the brain more effectively, hospitals could cut down on the dosage they need to administer.
“And if you can slow ALS progression and reduce disability in these patients, there is the potential to not only develop a much needed therapy, but [also] save our health-care system significant expense,” Dr. Lipsman adds.
And while it’s uncomfortable to lie in an MRI machine, this can be a painless and side-effect-free procedure for patients like Hanna.
To help others one day receive a truly effective treatment for this devastating disease, Hanna says undergoing the procedure as one of the first study participants was worth it.
“I would do it again,” she says.