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

J Neuroimmunol. 2024 Aug 15:393:578395. doi: 10.1016/j.jneuroim.2024.578395. Epub 2024 Jun 13.

Abstract

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.

Keywords: ACTH; Adrenoleukodystrophy; Bevacizumab; Blood-brain-barrier; VEGF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenoleukodystrophy / drug therapy
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use
  • Bevacizumab / pharmacology
  • Bevacizumab / therapeutic use
  • Blood-Brain Barrier* / drug effects
  • Blood-Brain Barrier* / metabolism
  • Child
  • Child, Preschool
  • Humans
  • Male
  • Vascular Endothelial Growth Factor A* / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A* / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • VEGFA protein, human
  • Angiogenesis Inhibitors