First-in-human trial of blood\u2013brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound

Agessandro Abrahao,Sandra E Black,Isabelle Aubert,Lorne Zinman,Yuexi Huang,Clement Hamani,Chinthaka Heyn,Ying Meng,Maheleth Llinas,Nir Lipsman,Kullervo Hynynen,Todd Mainprize

doi:10.1038/s41467-019-12426-9

Abstract

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.

Highlights

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
Two women and two men with median age 61 years, diagnosed with amyotrophic lateral sclerosis (ALS) and clinical evidence of upper motor neuron dysfunction were enrolled in the study (Fig. 1)
Each subject’s sonication targets (Supplementary Fig. 1) were individualized according to arm (Fig. 2a) or leg (Fig. 3a) functional MRI (fMRI) activation in the primary motor cortex to ascertain the homunculus topography

Summary

Introduction

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). This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. 5 Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada. 7 Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada. 8 Odette Cancer Research, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada. Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease characterized by the progressive degeneration of both the upper and lower motor neurons (UMNs and LMNs). An approved drug for ALS, has limited availability in the brain tissue given BBB-related drug efflux mechanisms[10]

Methods

Results

Conclusion