Abstract
Deficiencies of lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAG) cause pathologies commonly known as the mucopolysaccharidoses (MPS). Each type of MPS is caused by a deficiency in a specific GAG-degrading enzyme and is characterized by an accumulation of disease-specific GAG species. Previously, we have shown the potential of the beta-D-xyloside, odiparcil, as an oral GAG clearance therapy for Maroteaux-Lamy syndrome (MPS VI), an MPS characterized by an accumulation of chondroitin sulphate (CS) and dermatan sulphate (DS). This work suggested that odiparcil acts via diverting the synthesis of CS and DS into odiparcil-bound excretable GAG. Here, we investigated the effect of odiparcil on lysosomal abundance in fibroblasts from patients with MPS I and MPS VI. In MPS VI fibroblasts, odiparcil reduced the accumulation of a lysosomal-specific lysotracker dye. Interestingly, a reduction of the lysotracker dye was also observed in odiparcil-treated fibroblasts from patients with MPS I, a disorder characterized by an accumulation of DS and heparan sulphate (HS). Furthermore, odiparcil was shown to be effective in reducing CS, DS, and HS concentrations in liver and eye, as representative organs, in MPS VI and MPS I mice treated with 3 doses of odiparcil over 3 and 9 months, respectively. In conclusion, our data demonstrates odiparcil efficiently reduced lysosome abundance and tissue GAG concentrations in in vitro and in vivo models of MPS VI and MPS I and has potential as a treatment for these disorders.