Abstract
Mucopolysaccharidoses (MPS) are inherited, severe, progressive, metabolic disorders caused by deficiencies in different enzymes involved in degradation of glycosaminoglycans (GAGs). Although enzyme replacement therapy (ERT) has recently been available for MPS type I, and clinical trials have been performed in ERT for MPS II and MPS VI, there is little chance that this kind of treatment may be effective for neurodegenerative forms of MPS (due to inefficient delivery of enzymes to central nervous system through the blood–brain barrier), hence currently there is no effective therapy available for them. Therefore, we aim to develop an alternative therapy for these diseases. We found that genistein (4′,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) inhibits synthesis of GAGs considerably in cultures of fibroblasts of MPS patients (types I, II, IIIA and IIIB were tested). Prolonged cultivation of these cells in the presence of genistein resulted in reduction of GAG accumulation and normalization of cells as estimated by biochemical tests and electron microscopic analysis, respectively. As genistein inhibits kinase activity of epidermal growth factor receptor, which is required for full expression of genes coding for enzymes involved in GAG production, we propose to consider a substrate reduction therapy for MPS, which is referred to as ‘gene expression-targeted isoflavone therapy’.
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Acknowledgements
We are grateful to Jerzy Bohdanowicz for his help and advice in electron microscopic analyses. This work was funded by the British Society for Mucopolyssacharide Diseases (project no. J4G/25/04), Daniels Sanfilippo Fund (Grant no. DSF-UG-01/2005) and Polish Ministry of Education and Science (project no. 2 P05A 103 26). The use of genistein in treatment of mucopolysaccharidoses is a subject of patent application (application no. P-377180).
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Piotrowska, E., Jakóbkiewicz-Banecka, J., Barańska, S. et al. Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet 14, 846–852 (2006). https://doi.org/10.1038/sj.ejhg.5201623
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DOI: https://doi.org/10.1038/sj.ejhg.5201623
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