Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD) leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Franziska D Weber, Isabelle Weinhofer, Angelika Einwich, Sonja Forss-Petter, Zahid Muneer, Harald Maier, Willi H A Weber, Johannes Berger
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3cd89c0996e947dbad4aacf79f64a7c4
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3cd89c0996e947dbad4aacf79f64a7c4
record_format	dspace
spelling	oai:doaj.org-article:3cd89c0996e947dbad4aacf79f64a7c42021-11-25T06:06:30ZEvaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.1932-620310.1371/journal.pone.0103742https://doaj.org/article/3cd89c0996e947dbad4aacf79f64a7c42014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25079382/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD) leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance for X-ALD. In conclusion, our results suggest a change in promoter accessibility during macrophage differentiation allowing induction of ABCD2 by retinoids.Franziska D WeberIsabelle WeinhoferAngelika EinwichSonja Forss-PetterZahid MuneerHarald MaierWilli H A WeberJohannes BergerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e103742 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Franziska D Weber Isabelle Weinhofer Angelika Einwich Sonja Forss-Petter Zahid Muneer Harald Maier Willi H A Weber Johannes Berger Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
description	X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is a clinically heterogeneous disease that can manifest as devastating inflammatory cerebral demyelination (CALD) leading to death of affected males. Currently, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT is only effective when performed at an early stage because the inflammation may progress for eighteen months after HSCT. Thus, alternative treatment options able to immediately halt the progression are urgently needed. X-ALD is caused by mutations in the ABCD1 gene, encoding the peroxisomal membrane protein ABCD1, resulting in impaired very long-chain fatty acid metabolism. The related ABCD2 protein is able to functionally compensate for ABCD1-deficiency both in vitro and in vivo. Recently, we demonstrated that of the cell types derived from CD34+ stem cells, predominantly monocytes but not lymphocytes are metabolically impaired in X-ALD. As ABCD2 is virtually not expressed in these cells, we hypothesize that a pharmacological up-regulation of ABCD2 should compensate metabolically and halt the inflammation in CALD. Retinoids are anti-inflammatory compounds known to act on ABCD2. Here, we investigated the capacity of selected retinoids for ABCD2 induction in human monocytes/macrophages. In THP-1 cells, 13-cis-retinoic acid reached the highest, fivefold, increase in ABCD2 expression. To test the efficacy of retinoids in vivo, we analyzed ABCD2 mRNA levels in blood cells isolated from acne patients receiving 13-cis-retinoic acid therapy. In treated acne patients, ABCD2 mRNA levels were comparable to pre-treatment levels in monocytes and lymphocytes. Nevertheless, when primary monocytes were in vitro differentiated into macrophages and treated with 13-cis-retinoic acid, we observed a fourfold induction of ABCD2. However, the level of ABCD2 induction obtained by retinoids alone is probably not of therapeutic relevance for X-ALD. In conclusion, our results suggest a change in promoter accessibility during macrophage differentiation allowing induction of ABCD2 by retinoids.
format	article
author	Franziska D Weber Isabelle Weinhofer Angelika Einwich Sonja Forss-Petter Zahid Muneer Harald Maier Willi H A Weber Johannes Berger
author_facet	Franziska D Weber Isabelle Weinhofer Angelika Einwich Sonja Forss-Petter Zahid Muneer Harald Maier Willi H A Weber Johannes Berger
author_sort	Franziska D Weber
title	Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
title_short	Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
title_full	Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
title_fullStr	Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
title_full_unstemmed	Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.
title_sort	evaluation of retinoids for induction of the redundant gene abcd2 as an alternative treatment option in x-linked adrenoleukodystrophy.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/3cd89c0996e947dbad4aacf79f64a7c4
work_keys_str_mv	AT franziskadweber evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT isabelleweinhofer evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT angelikaeinwich evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT sonjaforsspetter evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT zahidmuneer evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT haraldmaier evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT willihaweber evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy AT johannesberger evaluationofretinoidsforinductionoftheredundantgeneabcd2asanalternativetreatmentoptioninxlinkedadrenoleukodystrophy
_version_	1718414156510527488

Evaluation of retinoids for induction of the redundant gene ABCD2 as an alternative treatment option in X-linked adrenoleukodystrophy.

Ejemplares similares