Critical review of current MPS guidelines and management.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that impair degradation of glycosaminoglycans (GAG). The specific GAGs that accumulate depend on the type of MPS, leading to unique characteristic clinical features. Development of guidelines for treatment of MPS has traditionally been multifaceted and largely based on palliative care. In the last three decades, hematopoietic stem cell transplantation and enzyme replacement therapy have been developed based on experimental and clinical studies. Guidelines have been established with the accumulation of the clinical data from natural history of the disease and therapeutic consequences, mainly sponsored by pharmaceutical companies. In recent years, committees in three countries, Australia (2015), Japan (2017), and Brazil (2018) have adopted guidelines for the treatment of MPS II, sponsored and authorized by each government. As novel treatments for MPS including substrate reduction therapy, pharmacological chaperone therapy, and gene therapy become clinically available, it is increasingly necessary to establish the optimal guideline for each type of MPS, considering multiple factors including therapeutic efficacy, adverse effects, age, disease stage, prognosis, feasibility and availability of access to treatment, and cost- performance. In this article, we discuss the historical guidelines for specific MPS types and the most recently adopted guidelines for MPS II and propose the development of future guidelines without conflict of interest and bias leading to mutual benefits to all parties including patients and families, professionals, tax payers, and governments.

Chaperone effect of sulfated disaccharide from heparin on mutant iduronate-2-sulfatase in mucopolysaccharidosis type II.

Small molecules called pharmacological chaperones have been shown to improve the stability, intracellular localization, and function of mutated enzymes in several lysosomal storage diseases, and proposed as promising therapeutic agents for them. However, a chaperone compound for mucopolysaccharidosis type II (MPS II), which is an X-linked lysosomal storage disorder characterized by a deficiency of iduronate-2-sulfatase (IDS) and the accumulation of glycosaminoglycans (GAGs), has still not been developed. Here we focused on the Δ-unsaturated 2-sulfouronic acid-N-sulfoglucosamine (D2S0), which is a sulfated disaccharide derived from heparin, as a candidate compound for a pharmacological chaperone for MPS II, and analyzed the chaperone effect of the saccharide on IDS by using recombinant protein and cells expressing mutated enzyme. When D2S0 was incubated with recombinant human IDS (rhIDS) in vitro, the disaccharide attenuated the thermal degeneration of the enzyme. This effect of D2S0 on the thermal degeneration of rhIDS was enhanced in a dose-dependent manner. D2S0 also increased the residual activity of mutant IDS in patient fibroblasts. Furthermore, D2S0 improved the enzyme activity of IDS mutants derived from six out of seven different mutations in HEK293T cells transiently expressing them. These results indicate that D2S0 is a potential pharmacological chaperone for MPS II.

A method for measuring disease-specific iduronic acid from the non-reducing end of glycosaminoglycan in mucopolysaccharidosis type II mice.

Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease-specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice.

Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease.

Pompe disease is an autosomal recessive myopathic disorder caused by the deficiency of lysosomal acid α-glucosidase (GAA). Recently, we showed that function of mutant GAA in fibroblasts derived from Pompe disease patient carrying c.546G>T mutation is improved by treatment with proteasome inhibitor bortezomib as well as pharmacological chaperone (PC). However, bortezomib-responsive GAA mutations are not fully characterized. In this study, we showed the effect of bortezomib on different mutants of GAA in patient fibroblasts and transiently expressed HEK293T cells. Bortezomib increased the maturation and residual activity of GAA in patient fibroblasts carrying PC-responsive M519V and PC-unresponsive C647W mutations. Enhanced colocalization of GAA with lysosomal marker LAMP2 was also observed in patient fibroblasts after treatment with bortezomib. When four distinct mutant GAAs, which show different response to PC, were overexpressed in HEK293T cells, bortezomib improved the activity of M519V, S529V, and C647W in them (1.3-5.9-fold). These results indicate that bortezomib enhances the activity of some PC-unresponsive GAA mutants as well as PC-responsive mutants.