MRI-guided Focused Ultrasounds Can Safely Open Brain-Blood Barrier in ALS Patients, Trial Shows

The non-invasive delivery of ultrasound waves in a controlled, targeted manner can be safely used to open the blood-brain barrier in people with amyotrophic lateral sclerosis (ALS), giving temporary access to their motor cortex, results from a first-in-human trial show.

The approach — called magnetic resonance guided focused ultrasound, or MRgFUS — may help overcome the main limitation of current systemic therapies for ALS, enabling them to cross the brain’s protective barrier and exert their effect where they are most needed.

The study, “First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound,” was published in Nature Communications.

MRgFUS is a new, non-invasive treatment method that uses magnetic resonance imaging (MRI) to guide the delivery of ultrasound waves — which pass safely through skin, bone, and muscle — to specific regions in the brain or other organs.

Ultrasound waves have a lot of energy. The spot where the sound waves converge is heated to temperatures that cause a controlled destruction of the targeted tissue without affecting the surrounding healthy tissues.

While the approach has been widely tested as a means to eliminate cancer tissue in a non-invasive manner, researchers have found that MRgFUS combined with fat microbubbles — injected intravenously before the procedure — may be used to disrupt the blood-brain barrier without heat-related injury, providing access for systemic treatments to specific regions of the brain.

The blood-brain barrier is a natural protective layer that regulates the transport between the brain’s blood vessels and the cells and other components that make up the brain tissue. Its role is to protect the brain from disease-causing pathogens and toxins that may be present in the blood. But this barrier is also a major obstacle to therapies targeting the brain.

InSightec, the company developing the MRgFUS approach, is already running multiple clinical trials in diseases like breast cancer brain metastasis, brain cancer, and Parkinson’s disease dementia to study the safety and feasibility of disrupting the blood-brain barrier using ultrasounds and microbubbles.

Now, researchers at the University of Toronto, in Canada, used the same mechanism in ALS patients, in the hopes they could disrupt the blood-brain barrier in the region that is most affected in these patients: the motor cortex.

“Therapeutic access to degenerating neurons and glial cells in the primary motor cortex is essential in the development of disease-modifying treatments in ALS,” the researchers said.

They conducted a first-in-human clinical trial (NCT03321487) with four ALS patients — two women and two men, median age 61 years — who had evidence of upper motor neuron abnormalities. MRgFUS was tailored according to the patients’ structural features and to brain damage seen on their MRI scans.

Evidence of any blood-brain barrier disruption was assessed with a contrast agent, called gadolinium, which leaked into the brain whenever the barrier was open.

The researchers found that the MRgFUS was able to open the barrier in a controlled “millimetre accuracy” manner, without increasing tissue temperature. The disruption was transient, with the amount of gadolinium decreasing one day after the procedure.

The barrier opening in the primary motor cortex was, in general, well-tolerated by the patients, who only experienced some mild-to-moderate procedure-related adverse events. Participants showed no changes in their neurological status during the procedure, nor during the following 24-hour period.

MRgFUS had no effect on the patients’ physical manifestations, and did not cause any changes in ALS progression course during the following 30 days.

Taken together, the results demonstrate that the BBB, or blood-brain barrier, “can be precisely, safely, and temporarily opened over a targeted region in the primary motor cortex in ALS subjects using transcranial MRgFUS,” the researchers said.

The team believes that “this study represents the seminal initial step in establishing a delivery platform whereby MRgFUS-mediated BBB opening can be coupled with the systemic administration of the most promising ALS therapeutics to directly target the degenerating motor cortex.”