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, it 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. Sanfilippo disease (MPS III) seems to be especially problematic as this condition is associated with severe learning difficulty and behavioral disturbance and only relatively mild somatic involvement. In most affected patients the progressive nature of the disease leads to death in the second (or rarely third) decade of life. As the disorder primarily affects the brain and nervous system, attempts to cure the disorder have not been possible and the best that can be currently offered is palliative or symptomatic care. Therefore, we aim to develop an alternative therapy for mucopolysaccharidoses. Apart from provision of the deficient enzyme, another possible strategy for treatment of lysosomal storage disorders (including MPS) is reduction of the substrate whose degradation is impaired. For such a substrate reduction therapy (SRT) an analogue of a monomer that is incorporated into a complex macromolecule is usually considered. It may be a competitor of the natural substrate for an enzyme synthesizing the macromolecule. However, in the process leading to synthesis of GAGs, the monomers are carbohydrates or their derivatives which are also involved in many other metabolic pathways. Therefore, a putative competitor that could block activity of one of enzymes taking part in GAG synthesis, would most probably interfere with many other metabolic pathways, by blocking other biochemical reactions, thus giving potentially serious side effects. Therefore, to avoid this problem, we aimed to develop SRT based on regulation of expression of genes coding for specific GAG synthetases. We found that genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), an isoflavone occurring naturally in relatively large amounts in soy, 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. Importantly, genistein is able to cross the blood-brain barrier to some extend. Since genistein inhibits kinase activity of epidermal growth factor (EGF) receptor, which is required for full expression of genes coding for enzymes involved in GAG production, we propose to consider a substrate deprivation therapy for mucopolysaccharidoses, which is referred to as "gene expression-targeted isoflavone therapy" (GET IT).

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/6313 must be provided.

1. The use of genistein in treatment of genetic diseases
2. SUBSTRATE DEPRIVATION THERAPY - ALTERNATIVE TREATMENT OF MUCOPOLYSACCHARIDOSES
3. EFFECT OF GENISTEIN SYNTHETIC DERIVATIVES ON REGULATION OF GLYCOSAMINOGLYCAN SYNTHESIS IN SANFILIPPO DISEASE (MUCOPOLYSACCHARIDOSIS TYPE III)