Technology development and preclinical research
Drs. Isabelle Aubert and Kullervo Hynynen, who collaborate on research into use of focused ultrasound to treat Alzheimer's disease, examine an ultrasound array being engineered in Hynynen's lab.
Before any therapeutic or medical device can be tested in people it must go through rigorous development and preclinical study to demonstrate feasibility and safety. Sunnybrook Research Institute (SRI) leads in fundamental research into focused ultrasound (FUS). In particular, it has unparalleled expertise in brain diseases, including Alzheimer’s disease.
In the early 1990s, Dr. Kullervo Hynynen, before joining SRI as director of Physical Sciences, began developing ultrasound applicators with multiple elements that could be powered separately for controlled heating of tissue deep within the body.
In 1992, Hynynen and his team first proposed the use of MRI with FUS to guide and monitor tissue damage, coining the term magnetic resonance-guided FUS. In doing so, they pioneered MRI-guided high-intensity FUS. This new technology harnessed the power of sound waves to heat and destroy targets deep inside the body, such as tumours or lesions while sparing healthy tissue, all without breaking skin.
Then in 1995, Hynynen and his team were the first to describe a controlled, reversible and reproducible means of using FUS to open the blood-brain barrier.
He and Dr. Ferenc Jolesz at Harvard University, considered by many to be the “father” of FUS, went on to show the feasibility of delivering ultrasound therapy noninvasively through an intact skull—something previously held to be impossible. To do this, they used a large, phased-array applicator for through-skull focusing and ablation.
In 1999, Hynynen partnered with GE Healthcare to spin off the technology. InSightec was thus founded. Seventeen years on, the ExAblate platform has now done more than 13,000 treatments for current indications and is used at more than 120 facilities. Most recently, in September 2016 the ExAblate Neuro became the first system to be approved by the U.S. Food and Drug Administration to treat patients with essential tremor.
Enter microbubbles
In 2001, Hynynen and colleagues showed that FUS paired with microbubbles could locally, transiently and reversibly disrupt the blood-brain barrier under MRI guidance. This was a huge step forward in treating brain diseases, given that 97% of drugs cannot pass through this protective barrier.
At SRI, Hynynen and Dr. Isabelle Aubert, a neuroscientist, used low-intensity FUS guided by MRI to deliver antibodies directly into the brains of mice with Alzheimer’s disease. Their research, published in 2010, was the first to show that the therapy shrank amyloid plaque, a telltale sign of the disorder. They have also used low-intensity FUS, alone and with therapeutics, to restore impaired cognitive function and spur the birth of new neurons. In each of these areas they were the first to attain such milestones. This work is moving steadily toward clinical trials.
Delivering therapies across the blood-brain barrier: focused ultrasound is applied through the skull to the brain region of interest. Microbubbles are injected into the bloodstream. When the bubbles reach the ultrasound field, they vibrate. This changes the property of the blood vessel wall, making it more permeable. This temporary effect allows therapeutic molecules like antibodies to move from the blood to the brain.
Illustration: Hang Yu Lin / Aubert lab
New directions
The research team continues to refine the technology and expand its reach. Hynynen’s lab is developing electronically steered, high-power phased arrays that, compared to mechanically positioned devices, can perform larger volumes of ablation and are cheaper to manufacture. Hynynen and Dr. Meaghan O’Reilly are also engineering technologies that combine therapeutic and diagnostic ultrasound. Here, ultrasound rather than the much more costly MRI is used to monitor treatment.
They are also studying how to expand clinical application of FUS. In cardiac care, Hynynen is investigating how FUS may be used to disrupt abnormal electrical conduction paths that cause tachycardia, an abnormally fast heart rate. Other applications under study include back pain, breast cancer, epilepsy, liver cancer, prostate cancer, stroke and trigeminal neuralgia.
In yet another application, Aubert led a proof-of-concept study in which her lab used MRI-guided FUS to deliver gene therapy noninvasively across the blood-spinal cord barrier, a major impediment to treating spinal cord injury or disease. Direct injection into the spinal cord has a high risk of complications. Using FUS, which is noninvasive, would greatly reduce these risks.
