Sanfilippo disease (mucopolysaccharidosis type III)
Sanfilippo disease belongs to the group of diseases called mucopolysaccharidoses, and it is also known as mucopolysaccharidosis type III, or MPS III [1]. Mucopolysaccharidoses (MPS) are inherited metabolic disorders, caused by mutations leading to dysfunction of one of enzymes involved in degradation of glycosaminoglycans (GAGs) in lysosomes [1,2]. Due to their impaired degradation, GAGs accumulate in cells of patients, which results in dysfunction of tissues and organs, including the heart, respiratory system, bones, joints and central nervous system (CNS). In Sanfilippo disease, clinical symptoms appear due to lysosomal storage of heparan sulfate (HS), one of the GAGs. This condition is associated with severe learning difficulties and behavioral disturbances, and with additional somatic involvement. In most affected patients the progressive nature of the disease leads to death in the second (or rarely third) decade of life. Until recently, attempts to cure the patients have not been successful and the best that could be offered was palliative or symptomatic care [2,3].
Soyfem – as a genistin-rich soy isoflavone extract – for treatment of Sanfilippo disease
Recent studies revealed that genistein (4', 5, 7-trihydroxyisoflavone or 5, 7-dihydroxy-3- (4-hydroxyphenyl)-4H-1-benzopyran-4-one) is an inhibitor of GAG synthesis in fibroblasts of patients suffering from mucopolysaccharidoses, including MPS III [4]. Moreover, a decrease in lysosomal GAG storage was noted after incubation of the cells with genistein at concentrations between 10 and 30 µM [4]. These results were a basis for investigation of genistein in studies on Sanfilippo diseases mouse model [5] and pilot clinical studies [6]. Experiments on mice documented efficacy of genistein in reduction of GAG storage in various tissues [5], while pilot clinical studies indicated that treatment of patients suffering from Sanfilippo disease with a genistein-rich isoflavone extract at the dose corresponding to the amount of genistein equal to 5 mg/kg/day resulted in statistically important improvement of all tested parameters, including cognitive functions [6]. After studies on animals, it appears that the dose of 10 mg/kg/day may be even more efficient than that used in the pilot clinical study.
The genistein-based substrate reduction therapy, called ‘gene expression-targeted isoflavone therapy’ (GET IT) because of inhibition of phosphorylation of epidermal growth factor receptor (EGFR) by genistein [7], appears a promising treatment [8], however, further clinical studies are necessary to optimize the dose and to estimate efficacy of this therapeutic option. In fact, a double-blinded placebo-controlled clinical trial is ongoing now. On the other hand, no other causal therapy for MPS III disease is currently possible.
In the recent pilot clinical study, mentioned above, a standardized soy isoflavone extract (SE-2000, product name: Soyfem, manufacturer: Biofarm, Poznań, Poland) was used, in which amounts of isoflavones were determined precisely [6]. Further studies indicated that this product fulfills all the quality requirements, and it is the only one which was employed in clinical studies, and one of very few (among several studied) commercially available products which were tested in vitro for their suitability for treatment of Sanfilippo disease and passed positively all the tests [9].
Literature cited:
1. Neufeld EF, Muenzer J. 2001. The mucopolysaccharidoses. In: The Metabolic and Molecular Bases of Inherited Disease, Scriver CR, Beaudet AL, Sly WS, Valle D (eds).McGraw-Hill Co: New York; 3421-3452.
2. Beck M. 2007. Mucopolysaccharidoses: clinical features and management. In: Genetic Metabolic Disorders: Management, Costs and Sociomedical Aspects, vom Dahl S, Wendel U, Strohmeyer G (eds). Deutscher Arzte-Verlag: Cologne; 13-18.
3. Beck M. 2007. New therapeutic options for lysosomal storage disorders: enzyme replacement, small molecules and gene therapy. Hum Genet 121: 1-22.
4. Piotrowska E, Jakóbkiewicz-Banecka J, Barańska S, Tylki-Szymańska A, Czartoryska B, Węgrzyn A, Węgrzyn G. 2006. Genistein-mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression-targeted isoflavone therapy for mucopolysaccharidoses. Eur J Hum Genet 14: 846-852.
5. Malinowska M, Wilkinson FL, Bennett W, Langford-Smith KJ, O’Leary HA, Jakóbkiewicz-Banecka J, Wynn R, Wraith JE, Węgrzyn G, Bigger BW. 2009. Genistein reduces lysosomal storage in peripheral tissues of Mucopolysaccharide IIIB mice. Mol Genet Metabol, in press.
6. Piotrowska E, Jakóbkiewicz-Banecka J, Tylki-Szymańska A, Liberek A, Maryniak A, Malinowska M, Czartoryska B, Puk E, Kloska A, Liberek T, Barańska S, Węgrzyn A, Węgrzyn G. 2008.
Genistin-rich isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: an open-label, pilot study in 10 pediatric patients. Curr Ther Res Clin Exp 69: 166-179.
7. Jakóbkiewicz-Banecka J, Piotrowska E, Narajczyk, M, Barańska S, Węgrzyn G. 2009.
Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway. J Biomed Sci 16: 26.
8. Jakóbkiewicz-Banecka J, Wegrzyn A, Wegrzyn G. 2007.
Substrate deprivation therapy: A new hope for patients suffering from neuronopathic forms of inherited lysosomal storage diseases. J Appl Genet 48: 383–388.
9. Piotrowska E, Jakóbkiewicz-Banecka J, Węgrzyn G. 2009.
Different amounts of isoflavones in various commercially available soy extracts in the light of gene expression-targeted isoflavone therapy. Phytother Res, in press.
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