Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy
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Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy. / Zierfuss, Bettina; Weinhofer, Isabelle; Kühl, Jörn-Sven; Köhler, Wolfgang; Bley, Annette; Zauner, Katharina; Binder, Johannes; Martinović, Ksenija; Seiser, Christian; Hertzberg, Christoph; Kemp, Stephan; Egger, Gerda; Leitner, Gerda; Bauer, Jan; Wiesinger, Christoph; Kunze, Markus; Forss-Petter, Sonja; Berger, Johannes.
in: ANN CLIN TRANSL NEUR, Jahrgang 7, Nr. 5, 05.2020, S. 639-652.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Vorinostat in the acute neuroinflammatory form of X-linked adrenoleukodystrophy
AU - Zierfuss, Bettina
AU - Weinhofer, Isabelle
AU - Kühl, Jörn-Sven
AU - Köhler, Wolfgang
AU - Bley, Annette
AU - Zauner, Katharina
AU - Binder, Johannes
AU - Martinović, Ksenija
AU - Seiser, Christian
AU - Hertzberg, Christoph
AU - Kemp, Stephan
AU - Egger, Gerda
AU - Leitner, Gerda
AU - Bauer, Jan
AU - Wiesinger, Christoph
AU - Kunze, Markus
AU - Forss-Petter, Sonja
AU - Berger, Johannes
N1 - © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
KW - ATP Binding Cassette Transporter, Subfamily D/drug effects
KW - ATP Binding Cassette Transporter, Subfamily D, Member 1/deficiency
KW - Acute Disease
KW - Adrenoleukodystrophy/cerebrospinal fluid
KW - Coenzyme A Ligases/drug effects
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Humans
KW - Inflammation/drug therapy
KW - Macrophages/drug effects
KW - Magnetic Resonance Imaging
KW - Outcome Assessment, Health Care
KW - Peroxisomes
KW - Vorinostat/pharmacology
U2 - 10.1002/acn3.51015
DO - 10.1002/acn3.51015
M3 - SCORING: Journal article
C2 - 32359032
VL - 7
SP - 639
EP - 652
JO - ANN CLIN TRANSL NEUR
JF - ANN CLIN TRANSL NEUR
SN - 2328-9503
IS - 5
ER -
