- Engelen Marc, Barbier Mathieu, Dijkstra Inge M. E., Schür Remmelt, de Bie Rob M. A., Verhamme Camiel, Dijkgraaf Marcel G. W., Aubourg Patrick A., Wanders Ronald J. A., van Geel Bjorn M., de Visser Marianne, Poll-The Bwee T., Kemp Stephan X-linked adrenoleukodystrophy in women: a cross-sectional cohort study Brain 2014;137 (Part 3):693-706 [PubMed]
- Kemp Stephan, Huffnagel Irene C., Linthorst Gabor E., Wanders Ronald J., Engelen Marc Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history Nature reviews. Endocrinology 2016;12 (10):606-615 [PubMed]
- Kemp Stephan, Berger Johannes, Aubourg Patrick X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE 2012;1822 (9):1465-1474 [PubMed]
- Kemp Stephan, Theodoulou Frederica L., Wanders Ronald J. A. Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance British journal of pharmacology 2011;164 (7):1753-1766 [PubMed]
- van de Beek Malu-Clair, Dijkstra Inge M. E., van Lenthe Henk, Ofman Rob, Goldhaber-Pasillas Dalia, Schauer Nicolas, Schackmann Martin, Engelen-Lee Joo-Yeon, Vaz Frédéric M., Kulik Wim, Wanders Ronald J. A., Engelen Marc, Kemp Stephan C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man PLoS ONE 2016;11 (4):e0154597 [PubMed]
S. Kemp PhD (Lipid metabolism and Neurotoxicity)
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 www.adrenoleukodystrophy.info
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.
Prof. R.J.A. Wanders PhD (Biochemistry & Enzymology of Metabolic Disorders)
M. Engelen PhD (Translational studies in (peroxisomal) leukodystrophies)
- SwanBio Therapeutics
- The GEIE ELA International