Mucopolysaccharidoses (MPSs) are rare inherited lysosomal storage diseases (LSDs) caused by deficient activity in one of the enzymes responsible for glycosaminoglycans lysosomal degradation. MPS II is caused by pathogenic mutations in the IDS gene, leading to deficient activity of the enzyme iduronate-2-sulfatase, which causes dermatan and heparan sulfate storage in the lysosomes. MPS VI has dermatan sulfate lysosomal storage, owing to a deficiency of arylsulfatase B, due to pathogenic mutations in the ARSB gene. Alterations in the immune system of MPSs mouse models have been described but the data is still scarce concerning MPSs patients. Herein, we study different leukocyte populations in MPS II and VI disease patients. MPS VI, but not MPS II patients, have a decrease percentage of Natural Killer (NK) cells and monocytes when compared with controls. No alterations were identified in the percentage of T, invariant NKT and B cells in both groups of MPS disease patients. However, we uncovered alterations in the naïve versus memory status of both helper and cytotoxic T cells in MPS VI disease patients compared to control group. Indeed, MPS VI disease patients have a higher frequency of naïve T cells and consequently lower frequency of memory T cells than control subjects. Altogether, these results reveal MPS VI disease-specific alterations in some leukocyte populations, suggesting that the type of substrate accumulated and/or enzyme deficient in the lysosome may have a particular effect on the normal cellular composition of the immune system.

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.