Abstract Details

To investigate for the first time the safety and feasibility of non-invasive MR-guided focused ultrasound (MRgFUS)-induced blood-brain barrier (BBB) opening in eloquent primary motor cortex in participants with amyotrophic lateral sclerosis (ALS).

The development of therapeutics that directly target cortical neurons and glia in ALS is essential in slowing disease progression; however, the BBB limits the delivery of therapeutics to the primary motor cortex. MRgFUS is a novel, noin-invasive technique that can accurately and transiently make the BBB permeable for targeted CNS drug delivery.

We conducted a single-arm, open-label, first-in-human trial evaluating MRgFUS-induced BBB opening of the motor cortex in four ALS volunteers. Patients were followed for two months, and safety was assessed using clinical and radiographic measures. Feasibility was assessed by gadolinium leakage at the site of sonication to confirm BBB opening. Clinical measures included motor, cognitive, and functional assessments in addition to general physical examination. Motor functional MRI, structural MRI, and EEG measures were also collected.

Successful BBB opening was achieved using MRgFUS in all subjects at the target site immediately post-sonication and normalized 24 hours later. The procedure was well tolerated with no serious adverse events. No unexpected ALS disease deterioration was noted. There was no radiological evidence of microhemorrhage or parenchymal lesion.

This study demonstrates for the first time that non-invasive BBB disruption over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, this procedure can be coupled with promising ALS therapeutics providing a novel delivery platform in ALS.