Abstract
Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a lysosomal storage disorder caused by deficiency of iduronate-2-sulphatase (IDS), resulting in glycosaminoglycans (GAG) accumulation and progressive multi-system pathology. Enzyme replacement therapy improves somatic manifestations but has limited neurological benefit. Therefore, pharmacological chaperone therapy has been proposed as a mutation-dependent strategy to stabilise misfolded IDS variants with residual activity. This study evaluated the effect of heparin octadecasaccharides (HO18) in patient-derived fibroblasts representing five genotypes and in HEK293T cells expressing IDS mutants. HO18 treatment (15 µM, 96 hours) produced mutation-specific effects across both experimental systems, with GAG reduction observed only in selected IDS variants. In fibroblasts carrying the p.Ile360Arg variant, IDS activity increased by approximately 1.8-fold along with a marked reduction in GAG levels (~71%). Other genotypes showed partial responses, including increased IDS activity without significant GAG reduction or GAG reduction in the absence of detectable IDS activity enhancement. In recombinant systems, HO18 increased IDS activity in p.Asn63Asp (~1.2-fold) and reduced GAG accumulation in p.Asn63Asp and p.Leu314Pro variants, while catalytically inactive mutants showed no response. Overall, HO18 exhibited pharmacological chaperone-like effects in selected IDS variants but also produced mutation-specific outcomes not fully explained by IDS activity enhancement alone. These findings support further in vitro investigation of HO18 as a mutation-dependent small-molecule approach for IDS-related pathology, while highlighting the need to better understand how HO18 acts and to confirm its effects in in vivo models.
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