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.