Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy

Bettina Zierfuss, Isabelle Weinhofer, J. rn-Sven Kühl, Wolfgang Köhler, Annette Bley, Katharina Zauner, Johannes Binder, Ksenija Martinović, Christian Seiser, Christoph Hertzberg, Stephan Kemp, Gerda Egger, Gerda Leitner, Jan Bauer, Christoph Wiesinger, Markus Kunze, Sonja Forss-Petter, Johannes Berger

Research output: Contribution to journalArticleAcademicpeer-review


Objective: To identify a pharmacological compound targeting macrophages, the most affected immune cells in inflammatory X-linked adrenoleukodystrophy (cerebral X-ALD) caused by ABCD1 mutations and involved in the success of hematopoietic stem cell transplantation and gene therapy. Methods: A comparative database analysis elucidated the epigenetic repressing mechanism of the related ABCD2 gene in macrophages and identified the histone deacetylase (HDAC) inhibitor Vorinostat as a compound to induce ABCD2 in these cells to compensate for ABCD1 deficiency. In these cells, we investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal β-oxidation activity, accumulation of very long-chain fatty acids (VLCFAs) and their differentiation status. We investigated ABCD2 and pro-inflammatory gene expression, restoration of defective peroxisomal ß-oxidation activity, accumulation of very long-chain fatty acids (VLCFA) and differentiation status. Three advanced cerebral X-ALD patients received Vorinostat and CSF and MRI diagnostics was carried out in one patient after 80 days of treatment. Results: Vorinostat improved the metabolic defects in X-ALD macrophages by stimulating ABCD2 expression, peroxisomal ß-oxidation, and ameliorating VLCFA accumulation. Vorinostat interfered with pro-inflammatory skewing of X-ALD macrophages by correcting IL12B expression and further reducing monocyte differentiation. Vorinostat normalized the albumin and immunoglobulin CSF-serum ratios, but not gadolinium enhancement upon 80 days of treatment. Interpretation: The beneficial effects of HDAC inhibitors on macrophages in X-ALD and the improvement of the blood-CSF/blood-brain barrier are encouraging for future investigations. In contrast with Vorinostat, less toxic macrophage-specific HDAC inhibitors might improve also the clinical state of X-ALD patients with advanced inflammatory demyelination.
Original languageEnglish
Pages (from-to)639-652
Number of pages14
JournalAnnals of Clinical and Translational Neurology
Issue number5
Early online date2020
Publication statusPublished - 1 May 2020

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