Bezafibrate for X-linked adrenoleukodystrophy

Marc Engelen, Luc Tran, Rob Ofman, Josephine Brennecke, Ann B. Moser, Inge M.E. Dijkstra, Ronald J.A. Wanders, Bwee Tien Poll-The, Stephan Kemp

Research output: Contribution to journalArticle

Abstract

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene and is characterized by impaired beta-oxidation of very-long-chain fatty acids (VLCFA) and subsequent VLCFA accumulation in tissues. In adulthood X-ALD most commonly manifests as a gradually progressive myelopathy, (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate (BF), a drug used for the treatment of hyperlipidaemia, reduces VLCFA accumulation in X-ALD fibroblasts by inhibiting ELOVL1, an enzyme involved in the VLCFA synthesis. We therefore designed a proof-of-principal clinical trial to determine whether BF reduces VLCFA levels in plasma and lymphocytes of X-ALD patients. Ten males with AMN were treated with BF for 12 weeks at a dose of 400 mg daily, followed by 12 weeks of 800 mg daily. Every 4 weeks patients were evaluated for side effects and blood samples were taken for analysis. Adherence was good as indicated by a clear reduction in triglycerides. There was no reduction in VLCFA in either plasma or lymphocytes. Plasma levels of BF did not exceed 25 μmol/L. We concluded that BF, at least in the dose given, is unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients. It is unclear whether this is due to the low levels of BF reached in plasma. Our future work is aimed at the identification of highly-specific inhibitors of ELOVL1 that act at much lower concentrations than BF and are well tolerated. BF appears to have no therapeutic utility in X-ALD. Trial Registration: ClinicalTrials.gov NCT01165060.

Original languageEnglish (US)
Article numbere41013
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 20 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Bezafibrate for X-linked adrenoleukodystrophy'. Together they form a unique fingerprint.

  • Cite this

    Engelen, M., Tran, L., Ofman, R., Brennecke, J., Moser, A. B., Dijkstra, I. M. E., Wanders, R. J. A., Poll-The, B. T., & Kemp, S. (2012). Bezafibrate for X-linked adrenoleukodystrophy. PloS one, 7(7), [e41013]. https://doi.org/10.1371/journal.pone.0041013