Mucopolysaccharidoses (MPS) are rare genetic, metabolic disorders caused by accumulation of mucopolysaccharides (glycosaminoglycans, GAGs) in lysosomes. This accumulation is caused by a deficiency in one of several specific enzymes involved in GAGs degradation. The disease causes severe problems in virtually all tissues and organs and usually leads to death in childhood. Currently, an effective treatment is available for MPS I (Aldurazyme^®) and clinical trials for MPS II and MPS VI have been completed. The treatment is based on administration of the lacking enzyme (enzyme replacement therapy, ERT). The delivery of enzyme molecules to the central nervous system is highly inefficient because of the blood-brain barrier. However, in many MPS types (MPS IH, MPS II, MPS IIIA, MPS IIIB, MPS IIIC, MPS IIID, MPS VII), central nervous system is also affected and ERT seems to be ineffective in treatment of neurological symptoms. The aim of this project is to develop an alternative, gene expression targeted isoflavone therapy (GET-IT), which could be used either alone or in combination with ERT. It seems that expression of at least some of genes coding for enzymes involved in GAGs degradation might be controlled through pathways, which are dependent on estrogen receptor protein and its tyrosine kinase activity (PTK). It has been reported that genistein (a natural soy isoflavone) inhibits activity of the tyrosine kinase (PTK). Basing on several human fibroblast culture experiments, we found that genistein and some of its synthetic derivatives inhibit GAG production up to ten times in fibroblasts of patients suffering from various types of MPS. We observed a significant decrease in levels of GAGs accumulated in fibroblasts of MPS III patients treated with genistein for several days. Moreover, genistein was reported to cross the blood-brain barrier in rats with efficiency of several percent after intravenous administration. It is of our interest to find out if any other natural isoflavones (e.g. daidzein, kaempferol, apigenin, naringenin) or genistein synthetic derivatives reveal inhibitory effects on GAGs synthesis, combined with a relatively high potential in blood-brain barrier penetration, especially in mucopolysaccharidosis IIIA and IIIB fibroblasts, as severe neurological injury is observed in these MPS types. We tested 20 synthetic genistein derivatives with MPS III human fibroblast cultures and 5 of them, presenting the highest inhibitory effect on GAG synthesis (similar to genistein or even higher) were chosen for further experiments. In conclusion, it appears that gene expression targeted isoflavone therapy (GET IT), based on administration of specific natural isoflavones or genistein synthetic derivatives, may potentially be an effective treatment of MPS III patients.

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1. The use of genistein in treatment of genetic diseases
2. SUBSTRATE DEPRIVATION THERAPY - ALTERNATIVE TREATMENT OF MUCOPOLYSACCHARIDOSES
3. GENE EXPRESSION-TARGETED ISOFLAVONE THERAPY FOR MUCOPOLYSACCHARIDOSES