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Clinical Trial
. 2019 Sep 26;10(1):4373.
doi: 10.1038/s41467-019-12426-9.

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

Agessandro Abrahao  1   2   3 , Ying Meng  4   5   6 , Maheleth Llinas  5   7 , Yuexi Huang  7 , Clement Hamani  4   5   6 , Todd Mainprize  6 , Isabelle Aubert  4   8 , Chinthaka Heyn  9   10 , Sandra E Black  11   4   7   12 , Kullervo Hynynen  7   10   12   13 , Nir Lipsman  4   5   6 , Lorne Zinman  11   4
Affiliations
Clinical Trial

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

Agessandro Abrahao et al. Nat Commun. .

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.

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Conflict of interest statement

N.L., K.H., and S.E.B. have received an honorarium from the Focused Ultrasound Foundation for serving on an expert steering committee on focused ultrasound in Alzheimer’s Disease. K.H. is an inventor on intellectual property owned by Brigham and Women’s hospital in Boston and Sunnybrook Research Institute in Toronto related to intracranial focused ultrasound technology. A.A., Y.M., M.L., C.Hamani, Y.H., T.M., I.A., C.Heyn, N.L., and L.Z. declare no competing interests.

Figures

Fig. 1
Fig. 1
Trial profile
Fig. 2
Fig. 2
Feasibility of blood–brain barrier opening using MRgFUS in the hand control region of the right primary motor cortex. a Hand control region mapping using motor-task functional MRI (fMRI). b, c show confirmation of successful blood–brain barrier permeabilization in the sonicated primary motor cortex area as demonstrated by new gadolinium enhancement in T1-weighted imaging. Subject two is represented in the top row and subject three in the bottom row
Fig. 3
Fig. 3
Feasibility of blood–brain barrier opening using MRgFUS in the leg control region of the right primary motor cortex. a Leg control region mapping using motor-task functional MRI (fMRI). b, c show confirmation of successful blood–brain barrier permeabilization in the sonicated primary motor cortex area as demonstrated by new gadolinium enhancement in T1-weighted imaging. Subject one is represented in the top row and subject four in the bottom row
Fig. 4
Fig. 4
Baseline and post-procedure gadolinium signal intensity ratio (IR) within the sonicated region on T1-weighted imaging. IRs were normalized to the contralateral, unsonicated mirrored region. Increased IRs were seen immediately after blood–brain barrier opening and returned to baseline within 24 h, indicating reversible BBB permeability. Raw data are provided in the Source Data file
See this image and copyright information in PMC

References

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