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

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.

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Copyright © 2024. Published by Elsevier B.V.

Déclaration de conflit d'intérêts

Declaration of competing interest AOG, JWF, DRN, SK, CJK, EEN, and WD have no conflicts. BSM is a consultant for Ascendis Pharma, BioMarin, Bristol Myers Squibb, EMD Serono, Endo Pharmaceuticals, Novo Nordisk, Pfizer, proventionbio and Tolmar and has received research support from Alexion, Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Lysogene, Novo Nordisk, OPKO Health, Pfizer, Prevail Therapeutics and Sangamo Therapeutics. PJO and TCL have been principle investigators with bluebird bio.