Mucopolysaccharidoses (MPS) are inherited disorders of glycosaminoglycan (GAG) metabolism caused by deficiency of certain lysosomal enzymes involved in GAG degradation. This inadequacy leads to storage of GAGs in most tissues, including brain in many types of MPS, and causing serious malfunction of organs. Enzyme replacement therapy (ERT), developed for a few of lysosomal storage disorders (LSDs), including three types of MPS, has been successful in treating somatic pathology and ameliorating clinical conditions of patients. However, since the intravenously injected enzyme is unable to cross the blood-brain barrier (BBB), disorders causing neurological impairment remain refractory. Substrate deprivation aims to reduce the intracellular load of substrate (GAG in MPS) for the deficient enzyme to digest, by decreasing the initial synthesis of the substrate. The soy isoflavone genistein was reported to affect, in an inhibitory way, the synthesis of GAGs via both estrogen receptor (ER) and protein tyrosine kinase pathway (PTK). Since genistein is a relatively small molecule and it was found to penetrate BBB, it should be considered as an alternative mean for MPS treatment. Here, GAG levels were measured in cell extracts of fibroblasts isolated from MPS I, MPS II, MPS IIIA and MPS IIIB patients as well as a control (healthy person) within several days of incubation with pure genistein, soy extract or Aldurazyme (a drug used in ERT for MPS I). Genistein was found to inhibit GAG synthesis in fibroblasts. Moreover, within several days, a considerable decrease in the amount of stored GAGs was observed in all types MPS cells (in MPS I fibroblasts the level of total GAG after genistein treatment was lowered comparably to the reduction gained with Aldurazyme). Therefore, administration of genistein may be considered as a possible supportive treatment of MPS, especially types in which central nervous system is affected and for which no clinical trials of ERT were yet initiated.

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1. The use of genistein in treatment of genetic diseases
2. EFFECT OF GENISTEIN SYNTHETIC DERIVATIVES ON REGULATION OF GLYCOSAMINOGLYCAN SYNTHESIS IN SANFILIPPO DISEASE (MUCOPOLYSACCHARIDOSIS TYPE III)
3. GENE EXPRESSION-TARGETED ISOFLAVONE THERAPY FOR MUCOPOLYSACCHARIDOSES