Bezafibrate for X-linked adrenoleukodystrophy

• Published in: PloS one Vol. 7; no. 7; p. e41013
• Main Authors: Engelen, Marc, Tran, Luc, Ofman, Rob, Brennecke, Josephine, Moser, Ann B, Dijkstra, Inge M E, Wanders, Ronald J A, Poll-The, Bwee Tien, Kemp, Stephan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20-07-2012; Public Library of Science (PLoS)
• Subjects: ABC transporters; Accumulation; Adrenoleukodystrophy; Adrenoleukodystrophy - drug therapy; Adrenoleukodystrophy - metabolism; Analysis; Bezafibrate; Bezafibrate - administration & dosage; Bezafibrate - pharmacology; Bezafibrate - therapeutic use; Bioaccumulation; Biology; Central nervous system diseases; Cholesterol; Chromatography; Clinical trials; Disease; Drug dosages; Enzymes; Fatty acids; Fibroblasts; Homeostasis; Humans; Hyperlipidemia; Hypolipidemic Agents - administration & dosage; Hypolipidemic Agents - pharmacology; Hypolipidemic Agents - therapeutic use; Laboratories; Lymphocytes; Male; Males; Mass spectrometry; Medical screening; Medical treatment; Medicine; Metabolic disorders; Mutation; Neurology; Oxidation; Patient compliance; Patients; Pediatrics; Plasma; Plasma levels; Reduction; Scientific imaging; Side effects; Spinal cord; Teaching hospitals; Tissues; Treatment Outcome; Triglycerides; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041013

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.
ClinicalTrials.gov NCT01165060.