| Summary: | Mucopolysaccharidoses result from genetic mutations in lysosomal enzymes required for degradation of glycosaminoglycans. The deficiency in any of eight lysosomal enzymes needed to degrade heparan sulfate leads to an accumulation of both non-degraded and partially degraded polysaccharides within the lysosomes of many tissues. Interestingly, six of these deficient enzymes can be treated by a relatively new approach – substrate reduction therapy (SRT), which aims to reduce the synthesis of the substrate for the deficient enzyme being targeted. I developed a cell-based high throughput screen assay for the identification of compounds that decrease the expression of the first modifying enzyme in HS biosynthesis, N-deacetylase/N-sulfotransferase 1, by inhibiting the transcription of its mRNA. From the high throughput screen, I identified several compounds, with a previous history of use in humans, which significantly decreased the endogenous NDST1 expression and therefore, could be considered as potential SRT agents for up to six Mucopolysaccharidoses.
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