Abstract
Mucopolysaccharidosis type II is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS) and characterized by the accumulation of the primary storage substrate, glycosaminoglycans (GAGs). Understanding central nervous system (CNS) pathophysiology in neuronopathic MPS II (nMPS II) has been hindered by the lack of CNS biomarkers. Characterization of fluid biomarkers has been largely focused on evaluating GAGs in cerebrospinal fluid (CSF) and the periphery; however, GAG levels alone do not accurately reflect the broad cellular dysfunction in the brains of MPS II patients. We utilized a preclinical mouse model of MPS II, treated with a brain penetrant form of IDS (ETV:IDS) to establish the relationship between markers of primary storage and downstream pathway biomarkers in the brain and CSF. We extended the characterization of pathway and neurodegeneration biomarkers to nMPS II patient samples. In addition to the accumulation of CSF GAGs, nMPS II patients show elevated levels of lysosomal lipids, neurofilament light chain, and other biomarkers of neuronal damage and degeneration. Furthermore, we find that these biomarkers of downstream pathology are tightly correlated with heparan sulfate. Exploration of the responsiveness of not only CSF GAGs but also pathway and disease-relevant biomarkers during drug development will be crucial for monitoring disease progression, and the development of effective therapies for nMPS II.
Highlights
Mucopolysaccharidosis type II (MPS II), known as Hunter syndrome, is a rare X-linked recessive lysosomal storage disease caused by a single gene defect resulting in a deficiency of iduronate-2 sulfatase (IDS) activity
In order to determine the relationship between brain and cerebrospinal fluid (CSF) GAGs in the setting of IDS deficiency, we utilized a mouse model of MPS II (Ids KO) [32] crossed with a chimeric mouse knock-in (KI) model expressing the human TfR apical domain (Ids KO;TfRmu/huKI; described in References [31,33]), treated with increasing doses of a TfR-mediated brain penetrant form of IDS, referred to as Enzyme Transport Vehicle:Iduronate-2-sulfatase fusion protein (ETV):IDS [31]
We focused on GM3 based on previous reports which showed an increase in GM3 levels, among other lysosomal lipids, in the brains of autopsied MPS II individuals [9], as well as our recently described work in a mouse model of MPS II [31]
Summary
Mucopolysaccharidosis type II (MPS II), known as Hunter syndrome, is a rare X-linked recessive lysosomal storage disease caused by a single gene defect resulting in a deficiency of iduronate-2 sulfatase (IDS) activity. Ganglioside and sphingolipid analysis from autopsied brain tissue show that individuals with increased lysosomal lipids in brain samples had the neuronopathic form of the disease [9] These data from patients suggest that monitoring CSF levels of GAGs and lysosomal lipids could provide a window to measure the effects of a candidate therapeutic on the CNS dysfunction. We utilized a well-characterized preclinical mouse model of MPS II treated with a novel brain Enzyme Transport Vehicle:Iduronate-2-sulfatase fusion protein (ETV:IDS) [31] to investigate the relationship between brain and CSF GAGs and downstream biomarkers of disease such as Nf-L. Sci. 2020, 21, 5188 stem cell transplantation (HSCT), have elevated CSF and serum Nf-L levels Taken together, these results open the possibility of monitoring Nf-L as a biomarker of treatment response for brain penetrant therapeutics such as ETV:IDS
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