First-in-human trial of blood–brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound

MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS.


Statistics
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Software and code
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Data collection
The 220 kHz ExAblate Neuro system type 2.0 software version 7.0 (InSightec, Israel) was used for all MR-guided focused ultrasound procedures (targeting, planing and sonications) and data collection.

Data analysis
The Statistical Parametric Mapping (SPM) software version 12 was used for the analysis of motor task fMRI. FreeSurfer (https://surfer.nmr.mgh.harvard.edu/) was used for volume estimation of the precentral gyrus.
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Data
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Life sciences study design
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Sample size
A cohort of four patients was planned for this early-phase trial. This sample size is typical for first-in-human surgical trials, where the objective is to demonstrate preliminary safety and technical feasibility. Given the small sample size, classic frequentist hypothesis testing based on p values was avoided to prevent type 1 errors and misleading inferences in this study which is underpowered to ascertain a mild or moderate treatment effect.
Data exclusions No data were excluded from the analyses. Randomization This is a single-armed study.

Blinding
This is an open-label study.
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Recruitment
Volunteers who contacted the study coordinator were pre-screened regarding their eligibility. All four volunteers who provided written informed consent and underwent the screening procedures were enrolled in the study. Efforts were made to balance sexes in this study.

Ethics oversight
The study was approved by the Research Ethics Board at Sunnybrook Health Sciences Centre (study number 453-2016) and Health Canada (ITA# 270370and CTA#207434).
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Outcomes
The primary outcome was safety and feasibility of transient BBB opening by MRgFUS in the primary motor cortex. Safety was measured as the occurrence and severity of device-and procedure-related, clinical or radiologic adverse events. Feasibility was qualitatively defined as detectable gadolinium enhancement signal into the sonicated targets on T1-weighted imaging immediately post-procedure, and resolution of the enhancement by the next day (reversibility criterion). Secondary outcome measures: feasibility was quantified by the gadolinium signal intensity ratio within a region of interest (ROI) in the targeted area, normalized to the contralateral, unsonicated mirrored ROI.