Substrate reduction therapy in a Drosophila melanogaster model of Sanfilippo syndrome

Sanfilippo syndrome, or mucopolysaccharidosis (MPS) types A, B, C or D, are neurodegenerative lysosomal storage disorders resulting from the lack of a specific enzyme involved in heparan sulfate (HS) catabolism. Several treatments are under evaluation for these conditions including substrate reduction therapy, with the most studied compound of this class being the isoflavone genistein. However, recent outcomes from a Phase III clinical trial have shown that high dose oral genistein does not significantly improve neurodevelopmental outcomes in MPS III patients. Here, we have tested an N-acetylglucosamine (GlcNAc) analogue inhibitor, 4-deoxy-GlcNAc peracetate, at reducing HS accumulation in cells from patients with Sanfilippo syndrome as a novel substrate reduction therapy. We then confirmed the capacity of this compound to modulate substrate accumulation in vivo in a Sanfilippo Drosophila model. Treatment with this compound significantly reduced HS in cultured MPS IIIA patient fibroblasts in a time-dependent manner. Neuronal and ubiquitous knockdown Drosophila models of MPS IIIC displaying elevated heparan sulfate and behavioural defects exhibited reduced HS burden relative to vehicle-treated controls following oral feeding with the GlcNAc analogue inhibitor. These findings indicate that this compound may be beneficial in slowing the accumulation of HS and may represent a novel therapeutic for Sanfilippo syndrome.