Our ALD research focuses on the following questions and objectives:
1) What is the role of VLCFA in the demyelinating process?
2) What is the genetic basis for the different phenotypes in ALD?
3) Which enzymes are important in the synthesis of VLCFA and how are they regulated?,
4) Development of a therapy for ALD, and
5) Provide reliable information on all aspects of ALD via .

During the last years we have:
• Developed methods to analyze synthesis VLCFA synthesis using stable-isotope labeled fatty acids and tandem mass spectrometry (Kemp et al., Mol. Genet. Metab. 2005)
• Identified ELOVL1, a key enzyme involved in VLCFA synthesis (Ofman et al., EMBO Mol. Med. 2010).
• Developed screening assay for the identification of compounds that inhibit VLCFA synthesis and/or toxicity.
• Generated a conditional transgenic mouse with an extra copy of the ELOVL1 that can be activated in a tissue specific to induce VLCFA synthesis (van de Beek et al PLoS One. 2016).
• Demonstrated that CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids (van Engen et al. Biochim Biophys Acta. 2016).
• Identified proteins that modulate VLCFA toxicity.
• Demonstrated that VLCFA can also be degraded via omega-oxidation. This pathway may function as an escape route (Sanders et al, J.Lipid.Res. 2005; J.Biol.Chem. 2006; FASEB J. 2008; van Engen et al. Biochim Biophys Acta. 2016).
• Conducted a placebo-controlled study with lovastatin in AMN patients to evaluate the effect of lovastatin on VLCFA in plasma and blood cells (Engelen et al. NEJM. 2010).
• Performed a large study to describe the clinical symptoms in women with ALD (Engelen et al Brain 2014).

The main focus for the research in the next years will be on: 1) the investigation of the therapeutic potential of pharmacological inhibition of VLCFA synthesis, 2) resolving the role that VLCFA play in the pathophysiology of ALD, and 3) the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.
Effective start/end date01/01/2010 → …

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