Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy

• Published in: Journal of neuroimmunology 2024-08, Vol.393, p.578395, Article 578395
• Main Authors: Gupta, Ashish O., Furcich, Justin W., Nascene, David R., Kemp, Stephan, King, Carina J., Nolan, Erin E., Durose, Willa, Miller, Bradley S., Orchard, Paul J., Lund, Troy C.
• Format: Article
• Language: English
• Subjects: ACTH; Adrenoleukodystrophy; Bevacizumab; Blood-brain-barrier; VEGF
• ISSN: 0165-5728; 1872-8421; 1872-8421
• DOI: 10.1016/j.jneuroim.2024.578395

The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically. •Adrenoleukodystrophy is caused by pathogenic variants in the X-linked ABCD1 gene.•High levels of ACTH and increases in permeability in endothelial cells.•An ACBD1 knockout endothelial cell line displayed increased sensitivity to ACTH.•anti-VEGF therapy produced decreased gadolinium contrast signal on MRI.•anti-VEGF therapy was insufficient to halt progression advanced cerebral ALD.