Mucopolysaccharidosis type II: preliminary data on glycosaminoglycan levels and structure in mice at baseline and after 6 weeks treatment with ERT

Mucopolysaccharidosis type II is a lysosomal storage disease due to the deficit of the enzyme iduronate 2-sulfatase (IDS) and to the consequent accumulation of heparan- (HS) and dermatan-sulfate (DS), with multi-organ involvement. In this study we characterized glycosaminoglycan (GAG) levels and structure in the brain and liver of the Ids knock-out mouse model, at 12 weeks of age and after 6 weeks treatment with human IDS (hIDS) enzyme, by using the capillary electrophoresis-laser induced fluorescence (CE-LIF) technique. As expected, Ids-ko mice showed a heavy accumulation of HS, about 15 times higher than wild-type (wt) in the brain and up to 240 times in the liver. The overall HS charge density rose by 1.5 times only in the liver, but the sulfation pattern changed in both organs. We also observed an increased chondroitin-sulfate (CS)+DS levels of about 2 times in the brain and 5 times in the liver, but an increased CS/DS ratio of about 22 times only in the liver. On the contrary, the hyaluronic acid (HA) levels did not change in both organs. We also conducted the same analysis in Ids-ko mice treated with 1 mg/kg of hIDS, once a week. As expected, we observed in the liver a huge reduction of HS (20 times vs untreated mice) and also of CS+DS and CS/DS. Instead, we did not observe a reduction of the different GAGs in the brain, confirming the enzyme inability to cross BBB. In this district a slight increase of CS/DS ratio, CS+DS and HA levels, and an about 40% increase of HS level, vs untreated ko mice, was observed. On the opposite, the overall HS charge density is decreased 2.5X vs untreated ko and wt mice. This preliminary data underline how by using a more sensitive technique of analysis, a clear separation of the GAGs pattern between wt and Ids-ko mice can be observed. This results particularly important for the brain, where application of common biochemical techniques detects very low GAG levels in both animal types, thus limiting the use of GAG analysis as possible biomarker of therapeutic efficacy in the brain district. The application of CE-LIF analysis is therefore proposed for a detailed evaluation of GAG pattern for potential monitoring of therapeutic efficacy.