Storage correction in cells of patients suffering from mucopolysaccharidoses types IIIA and VII after treatment with genistein and other isoflavones

Abstract

Mucopolysaccharidoses are autosomal and recessive lysosomal storage disorders caused by the deficiency of a lysosomal enzyme involved in glycosaminoglycan catabolism. The Sanfilippo type A disease (MPS III A) results from sulfamidase deficiency, which leads to accumulation of heparan sulfate, whereas Sly disease (MPS VII) results from beta-glucuronidase deficiency, leading to accumulation of heparan, dermatan, and chondroitin sulfates. These syndromes are characterized by severe central nervous system degeneration, resulting in progressive mental retardation, and fatality occurs in severely affected children. To date, no effective treatment is available except for bone marrow transplantation in specific cases. Recently, the use of genistein, an isoflavone that inhibits glycosaminoglycans synthesis, has been tested as substrate reduction therapy for neuronopathic forms of these diseases.We tested five natural analogs to genistein in human fibroblasts from both Sanfilippo A and Sly patients. Four molecules were as efficient as genistein in decreasing glycosaminoglycan accumulation. Moreover, a combination of several isoflavones was more efficient than one single isoflavone, suggesting a synergistic effect. These preliminary data may offer new perspectives for treating Sly and Sanfilippo A diseases and could be relevant to other neurological forms of mucopolysaccharidoses.

The Phytoestrogen Genistein Modulates Lysosomal Metabolism and Transcription Factor EB (TFEB) Activation

“…Therefore, the final effect of genistein action is a decreased efficiency of production of chondroitin/dermatan, heparan, and keratan sulfates. This conclusion is corroborated by the results of earlier biochemical analyses (7,11,36). The altered expression signatures point to inhibition of signaling pathways as important targets for genistein, a candidate for mucopolysaccharidosis-inhibiting agent.…”

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

“…Some other flavonoids were also able to decrease GAG storage in MPS IIIA, IIIB, and VII cells (Arfi et al 2010;Piotrowska et al 2010;Kloska et al 2011). Similar to rhodamine B, genistein caused a marked improvement in treated MPS IIIB mice, particularly in decreasing GAG storage in various organs (Malinowska et al 2009) and in correction of otherwise severely changed behavior (Malinowska et al 2010).…”

Gene expression‐targeted isoflavone therapy

“…Other isoflavones (formononetin, daidzein, biochanin A, and glycitein) were also effective in decreasing GAG storage in fibroblasts derived from patients suffering from MPS types IIIA and VI (24). Interestingly, combinations of various isoflavones were more effective in reducing GAG storage than any one single isoflavone (24).…”

“…Other isoflavones (formononetin, daidzein, biochanin A, and glycitein) were also effective in decreasing GAG storage in fibroblasts derived from patients suffering from MPS types IIIA and VI (24). Interestingly, combinations of various isoflavones were more effective in reducing GAG storage than any one single isoflavone (24). This unexpected phenomenon of synergistic action of isoflavones might be explained by results of recent experiments, which indicated that other flavonoids, unlike genistein, can decrease efficiency of GAG synthesis in reactions independent on EGF receptor autophosphorylation (25).…”