Year: 2024
Type: article
Study design: Clinical Trial
Abstract: Cerebral endothelial cell (EC) injury and blood-brain barrier (BBB) permeability contribute to neuronal injury in acute neurological disease states. Preclinical experiments have used animal models to study this phenomenon, yet the response of human cerebral ECs to BBB disruption remains unclear. In our phase I clinical trial (ClinicalTrials.gov NCT04528680), we used low-intensity pulsed ultrasound with microbubbles (LIPU/MB) to induce transient BBB disruption of peritumoral brain in patients with recurrent glioblastoma. We found radiographic evidence that BBB integrity was mostly restored within 1 hour of this procedure. Using single-cell RNA sequencing and transmission electron microscopy, we analyzed the acute response of human brain ECs to ultrasound-mediated BBB disruption. Our analysis revealed distinct EC gene expression changes after LIPU/MB, particularly in genes related to neurovascular barrier function and structure, including changes to genes involved in the basement membrane, EC cytoskeleton, and junction complexes, as well as caveolar transcytosis and various solute transporters. Ultrastructural analysis showed that LIPU/MB led to a decrease in luminal caveolae, the emergence of cytoplasmic vacuoles, and the disruption of the basement membrane and tight junctions, among other things. These findings suggested that acute BBB disruption by LIPU/MB led to specific transcriptional and ultrastructural changes and could represent a conserved mechanism of BBB repair after neurovascular injury in humans.
Source: JCI Insight
Authors: Andrew Gould, Yu Luan, Ye Hou, Farida V. Korobova, Li Chen, Victor A. Arrieta, Christina Amidei, Rachel Ward, Cristal Gomez, Brandyn Castro, Karl Habashy, Daniel Zhang, Mark Youngblood, Crismita Dmello, John Bebawy, Guillaume Bouchoux, Roger Stupp, Michael Canney, Feng Yue, M. Luisa Iruela-Arispe, Adam M. Sonabend
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Awards: G1164661550, G1284175734, G1382277591, G1697802790, G1707314010, G1743969612, G1902290544, Blood-brain barrier disruption with implantable ultrasound to enhance paclitaxel delivery: A Phase 1-2 clinical trial in recurrent glioblastoma, G317886719, G4159268500, G4407194527, MAPK as target of glioma immunoediting by CD8 T-cells, and predictor of response to immunotherapy, Advancing treatment and understanding of immunotherapy in glioblastoma, G4956023974, G6544658276, G9000046704, G9000061971, SPORE for Translational Approaches to Brain Cancer, G9000243610, The Robert H. Lurie Comprehensive Cancer Center
OpenAlex ID: W4405802973