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10 1016@bs Accb 2019 09 001
10 1016@bs Accb 2019 09 001
Mucopolysaccharidosis type II
(Hunter syndrome): Clinical and
biochemical aspects of the disease
and approaches to its diagnosis
and treatment
Shifaza Mohamed, Qi Qi He, Arti A. Singh, Vito Ferro*
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
*Corresponding author: e-mail address: v.ferro@uq.edu.au
Contents
1. Introduction 2
1.1 Lysosomal storage diseases (LSDs) 2
1.2 Mucopolysaccharidoses (MPS) and glycosaminoglycans (GAGs) 3
2. Mucopolysaccharidosis type II (MPS II) 4
2.1 History and incidence of MPS II 4
2.2 Genetics of MPS II 8
2.3 Clinical aspects of MPS II 8
3. Biochemical basis of disease 13
3.1 Iduronate-2-sulfatase (IDS): Structure, substrate specificity, and enzyme
mechanism 13
3.2 Mutational analysis of IDS in MPS II 16
4. Diagnostic methods for MPS II 18
4.1 Overview 18
4.2 Development of IDS enzyme activity assays 19
4.3 Assays based on biomarkers of MPS II 27
5. Management and treatment of MPS II 30
5.1 Overview 30
5.2 Enzyme replacement therapy 30
5.3 Substrate reduction therapy 32
5.4 Pharmacological chaperone therapy 33
5.5 Other treatments 34
6. Conclusions 35
Acknowledgments 36
References 37
1. Introduction
1.1 Lysosomal storage diseases (LSDs)
Lysosomes are the organelles responsible for the intracellular degradation of
macromolecules such as oligosaccharides, glycolipids, proteins and glyco-
proteins; their optimal functioning is crucial for cellular homeostasis. Lyso-
somal storage diseases (LSDs) are hereditary disorders caused by specific
mutations in genes encoding lysosomal enzymes, with approximately 50 dif-
ferent LSDs currently known.1 In several cases, the mutated enzymes are
catalytically competent but are misfolded and are thus more rapidly degraded
by cellular proteases within the endoplasmic reticulum-associated degrada-
tion machinery, leading to reduced lysosomal trafficking. This results in the
progressive intra-lysosomal accumulation of undegraded or partially
degraded substrate(s) of the defective enzymes, giving rise to severe clinical
phenotypes that ultimately lead to cell and tissue damage. LSDs are generally
classified according to the major storage material(s) or the nature of the
underlying lysosomal defect(s) (Table 1).1–4
uronic acid residue, either D-glucuronic acid or L-iduronic acid (IdoA) and
an amino sugar, either D-glucosamine or D-galactosamine.17,22 There are
four classes of sulfated GAGs: heparan sulfate (HS), dermatan sulfate (DS),
chondroitin sulfate (CS) and keratan sulfate (KS). Hyaluronic acid, or
hyaluronan, is a unique non-sulfated GAG.17,22
GAGs destined for lysosomal degradation travel through the endosomal
network after endocytosis, following which GAG degradation occurs
through enzyme-mediated exoglycosidic cleavage of specific terminal sugars
and desulfation of sulfated residues (Figs. 1 and 2). The resulting monosac-
charides and inorganic sulfate generated from complete degradation are then
actively transported out of the lysosome. In the case of MPS-affected indi-
viduals, different substrates are accumulated in their lysosomes depending on
the specific enzyme deficiency.
Eleven known lysosomal deficiencies result in seven distinct forms of
MPS (Table 2).5,22–24 With the exception of MPS IIIC, which is caused
by the deficiency of a transferase, these disorders are caused by deficiency
in one of the glycosidase or sulfatase enzymes.
Some of the physiological processes that may be affected by defective
GAG degradation and GAG-filled lysosomes include additional lysosomal
storage by interference of lysosomal hydrolases; altered plasma-membrane
receptor assembly; altered sequestration of growth factors; altered sequestra-
tion, recruitment and presentation to signaling receptors of cytokines;
abnormal extracellular matrix crosslinks; altered cell attachment and inter-
ference with cellular trafficking; and macrophage dysfunction.22 Each
MPS disease is characterized by progressive multisystem involvement with
key morbid manifestations involving the skeleton, joints, somatic tissues,
heart and, in some disorders, the central nervous system (CNS).22–26 Fur-
thermore, each of the disorders is characterized by a spectrum of disease
manifestations and clinical severity, which ranges from early onset with rapid
progression to attenuated forms with later onset and slow progression. The
disease spectrum seen in MPSs can be attributed to the differences in residual
enzyme activity.
Fig. 1 Degradation of heparan sulfate (HS). Large HS chains are first degraded
into smaller fragments by an endo-β-glucuronidase (heparanase), followed by a
well-ordered sequential degradation, one monosaccharide unit at a time from the
non-reducing end. Reproduced with permission from Varki, A., et al., Eds. Essentials
of Glycobiology, 2nd ed.; Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press,
2009 by The Consortium of Glycobiology Editors, La Jolla, California.
mostly males, its incidence has been reported to range from one per 500,000
to one per 92,000 live births, depending on the population studied.6,16,27
The disease that now bears his name was first documented by Charles
Hunter in 1917,29 when he described its physical features in two brothers.
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Fig. 2 Degradation of dermatan sulfate (DS) and chondroitin sulfate (CS). Reproduced
with permission from Varki, A., et al., Eds. Essentials of Glycobiology, 2nd ed.; Cold Spring
Harbor (NY): Cold Spring Harbor Laboratory Press, 2009 by The Consortium of Glycobiology
Editors, La Jolla, California.
2.3.2 Development
Infants with MPS II appear normal at birth and may achieve early develop-
mental milestones, even in the presence of acute somatic disease. Develop-
mental delays generally become apparent by 18–24 months of age, with very
slow progress thereafter; most patients hit a developmental plateau between
3 and 5 years of age.27 The disease has been found to considerably impact
both the physical and psychological aspects of the quality of life of both
patients and their family members,63,69 with some affected children dis-
playing aggression and hyperactivity, and teenagers and young adults
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Fig. 3 IDS cleaves the C-2 sulfo group of terminal IdoA residues in HS (top) and DS (bottom).
the entire protein length, (b) a highly conserved N-terminal region con-
taining the sulfatase motif, and (c) a unique active-site aldehyde residue,
α-formylglycine (FGly).110 The IDS enzyme has recently been crystallized
and its X-ray crystal structure solved to 2.3Å resolution110a; and some
homology models have also been constructed (see below). Various studies
have been conducted on the topography of the active site,111 as well as
on enzyme kinetics and physical properties of the enzyme.112 The catalytic
pocket of the enzyme is believed to contain a divalent metal cation and to be
lined with several positively charged residues that facilitate the anionic sul-
fate binding, with the FGly residue resting at the bottom of this pocket as the
aldehyde hydrate. The FGly residue is essential for IDS catalytic activity and
is generated post-translationally by oxidation of a cysteine precursor found
in the encoded peptide sequence of the enzyme. The minimum consensus
motif that allows the conversion of cysteine to FGly is formed by 11 amino
acids that form the core motif C(X/T)P(X/S)R, which is highly conserved
among most sulfatases from all species.113,114 It has been shown that the oxi-
dation event occurs during later co- or post-translation, after translocation to
the endoplasmic reticulum and before protein folding. Mutations in the
active site or in the flanking regions lead to decreased substrate affinity or
enzyme stability.51
Fig. 4 shows the catalytic mechanism for the cleavage of the sulfate ester
bond of the terminal IdoA residues of HS and DS by IDS. The aldehyde
hydrate catalytic form of the FGly residue in the active site is formed by
the addition of a water molecule to the formyl group. Transesterification
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of the sulfate group of the substrate on to the enzyme then results in an FGly
sulfate adduct (left). Subsequent elimination of the sulfate group by the reac-
tion of the second geminal hydroxyl group of the intermediate and the
cleavage of the C–O bond regenerates the aldehyde (top).115
In 1990, Hopwood and co-workers substantially purified IDS more than
500,000-fold in 5% yield from human liver, lung, kidney and placenta, and
identified two major forms of IDS, form A and form B.112 Form A and
form B had almost the same recovered enzyme activities toward a series
of substrates derived from heparin, HS and DS, but with different molecular
masses of 42 kDa and 14 kDa, respectively. Kinetic parameters of form A
were determined with a variety of substrates derived from HS, heparin
and DS. It was found that the structure of the residue next to the non-
reducing end of the IdoA-2-sulfate (IdoA2S) residue significantly affected
the IDS enzyme’s catalytic efficiency and binding affinity. Heparin-derived
tetrasaccharide substrates with a 6-O-sulfo group on the adjacent glucos-
amine residue were hydrolyzed with up to 200 greater efficiency than
those without sulfation at this position. A GlcNS substituent also increased
the binding affinity by up to twofold compared with GlcNAc or GlcNH.
The simplest disaccharide substrate tested for IDS activity was
IdoA2S-anM (1, Fig. 5). The related substrate IdoA2S-anM6S (2) with
an additional sulfate on the anhydromannitol residue was hydrolyzed by
IDS with a 63-fold increase in catalytic efficiency and a fivefold increase
in binding affinity.114 There are only a few known competitive inhibitors
of IDS (see also Section 5.4), including compounds derived from degrada-
tion of heparin (3–7) and ascorbic acid sulfate 8.111,112 The most potent
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Fig. 5 Structures of substrates (1–2) and inhibitors (3–8) of IDS with Ki values at pH 4.5.
et al.54 utilized the same homology model to investigate IDS mutations and
polymorphisms in a Tunisian MPS II-affected family.
Kato et al. (2005)51 then investigated the genotype–phenotype relation-
ships of IDS gene mutations in 18 MPS II patients in Japan by carrying out a
mutational and structural analysis of the IDS gene using an IDS homology
model created based on the structure of arylsulfatase A. A total of 16 muta-
tions were identified, with seven of these being novel.51 Mutations identi-
fied from the severe clinical phenotype included four missense mutations
and one nonsense mutation. Mutations from the attenuated phenotype
included four missense mutations, two nonsense mutations, three frame shift
mutations, one splice site mutation, and one amino acid deletion. IDS muta-
tions in severely affected individuals had significant influences on the tertiary
structure of the IDS protein, resulting in loss of IDS enzyme activity,51 while
most mutations in the attenuated patients only partially affected the protein
structure with preservation of residual enzyme activity, leading to the
observed milder clinical phenotype.51
Further investigation of genotype–phenotype correlations by Sukegawa-
Hayasaka et al.52 in 2006 focused on 11 common IDS missense mutations
identified in MPS II patients. Mutant IDS proteins with these mutations
were produced in CHO cells, and enzyme activity, protein processing,
and structural analyses were conducted using an engineered reference
IDS protein and a homology model based on the human arylsulfatases
A and B.52 Mutant proteins in the attenuated MPS II phenotype were found
to have residual enzyme activity (0.2%–2.5% of wildtype), while mutants in
the severe clinical phenotype had none.52 In addition, the mutations con-
siderably changed the structural conformation of the IDS protein, leading
to its degradation and/or insufficiency in protein processing.52 These find-
ings about the distribution of IDS mutations and their effects on the pro-
tein structure have considerable impacts on the selection of the available
therapies for MPS II patients, as well as for the design and development of
new MPS II treatments (see Section 5.4). Saenz et al.116 have also reported
the construction of a homology model of IDS based on arylsulfatases
A and B.
Galvis et al. carried out protein modeling and molecular docking simu-
lations on wildtype and mutant forms of IDS to investigate the effects of
mutations on enzyme structure and functions, and to identify correlations
between genotype and phenotype among Colombian MPS II patients.57
In this study, a homology model was constructed using arylsulfatase A as
the template. Molecular docking was carried out on IDS mutants with
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HS and DS ligands, although it was not clear what size fragments were used.
These studies identified putative active site residues and showed that muta-
tions affected protein conformation and substrate–protein interactions,
suggesting implications for protein stability, processing and trafficking to
lysosomes.57
Scheme 2 Reaction scheme for fluorometric assay for IDS enzyme activity.
Scheme 3 IDS enzyme product of substrate 17 and its CID ion products.
the benzoyl group. ESI-MS/MS can then detect and quantify product ions
19a and 19b, after collision-induced dissociation (CID) of the 6-sulfate
group present in the 2,5-anhydromannosyl residues (80 Da mass difference).
This ESI-MS/MS assay proved to be sensitive, only required a small amount
of sample, and had the capability for multiplexing to assay several different
lysosomal enzymes for LSDs. However, a potential limitation of this assay is
the interfering effect of other lysosomal or non-lysosomal enzymes present
in DBS. In addition, it was impractical to attain the amount of substrate 17
needed to support worldwide newborn screening for MPS II due to the dif-
ficulties with scale-up preparation of 17 using the nitrous acid degradation of
heparin.
Thus, Gelb and co-workers developed a new method for large-scale
preparation (tens of grams per year) of appropriate substrates for
IDS.136,137 The common structural features of the substrates are (1) a group
that is specifically recognized by the enzyme, (2) a hydrophobic carbon
chain as part of the enzyme-generated product that allows chromatographic
separation, and (3) a readily fragmentable functional group that leads to a
dominant fragmentation pathway in the mass spectrometer (improving assay
sensitivity). The target substrate α-L-iduronidate-2-sulfate glycoside 23
(Scheme 4) consists of an umbelliferyl group bearing a hydrophobic linker
with a terminal tert-butyloxycarbamate group. The substrates were synthe-
sized starting from α-L-iduronate glycoside methyl ester 20, prepared pre-
viously by the Gelb group using a nine-step synthetic sequence.123
Amide coupling with a Boc-protected diamine to give 21 was followed
by selective sulfation at the C-2 position via the stannylene acetal 22 and
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Scheme 4 Synthesis of IDS substrates and internal standard for ESIMS/MS (A) and the
resulting CID ion products (B).
deprotection of the methyl ester to give target substrates 23a and 23b.136
Substrate 23b has a longer hydrophobic carbon chain than that of 23a,
which results in better purification by HPLC, and is thus the preferred sub-
strate. Substrate 23b can be used to assay IDS enzyme activity using either a
fluorometric assay (see Section 4.2.2) or an ESI-MS/MS assay (this section).
The former is made possible by the presence of the umbelliferyl moiety,
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Scheme 5 (A) Synthesis of IDS substrate 30 for ESIMS/MS assay; (B) diagnostic fragment
ion from CID of product 31 following cleavage of 30 by IDS; (C) diagnostic fragment ion
from CID of aglycone 34 following cleavage of 31 by α-L-iduronidase.
different chemical species is greatly reduced, and the size of the molecules is
much smaller. This is crucial for MS analysis, as small molecules are more
amenable to standard reversed-phase separation and subsequent MS analysis.
Tomatsu et al. demonstrated that for MPS I, II, III, and VI the characteristic
accumulation of GAGs is represented by increased levels of HS and DS
derived disaccharides in plasma.142,143
The function of IDS is to hydrolyze the C2-sulfate of IdoA residues at
the non-reducing end of HS and DS, and thus, the HS- and DS-derived oli-
gosaccharides from MPS II patients have non-reducing end iduronate-
2-sulfate. Fuller et al. used ESI-MS/MS to identify di- to pentasaccharides
isolated from urine samples of MPS II patients.144 Oguma et al. reported the
development of an HPLC-ESI-MS/MS method capable of detecting
nanomolar amounts of HS- and DS-derived disaccharides in serum and
plasma and showed that these disaccharides are elevated approximately
5- to 10-fold in MPS II patients compared to unaffected controls.143 This
method requires digestion of sample GAGs to disaccharides with bacterial
endo-enzymes prior to analysis. Pan et al. developed an LC-MS/MS
assay to quantify the elevated DS levels in the CSF of MPS II patients
compared with controls. DS was quantified by ion-pairing LC-MS/MS
analysis of the major disaccharides, DS46 and DS6S, from digestion with
chondroitinase B.145 In 2010, Fuller and co-workers developed an
HPLC-MS/MS assay for determining intact HS- and DS-derived di- to
pentasaccharides that they previously identified in MPS II urine, as
3-methyl-1-phenyl-5-pyrazolone derivatives.146 It was found that the ele-
vated levels of each of the oligosaccharides enabled a complete differenti-
ation of the MPS II patients from unaffected controls.146 Furthermore, a
number of oligosaccharides were more abundant in MPS II patients with
CNS involvement compared with patients without CNS disease. Recently,
following technological improvements in HPLC, Fuller and co-workers
have expanded this method to diagnose 10 MPS subtypes with 100% spec-
ificity and sensitivity.147 Identification of MPS II is reliant on the presence
of a diagnostic sulfated disaccharide UA-HNAc (1S).
In 2012, Lawrence et al. developed an approach for diagnosis of MPS
disorders including MPS II by determining the characteristic non-
reducing end structures of GAGs as diagnostic biomarkers.148 Lysosomal
degradation of GAGs occurs in an ordered manner from the non-reducing
end of the chains. Thus, absence of any one enzyme in the pathway results
in the accumulation of characteristic non-reducing terminal carbohydrate
structures. The approach involved liberating sets of disease-specific
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biomarkers derived from the non-reducing ends of the GAGs that accu-
mulate in MPS patients. These biomarkers were then readily distinguished
from internal segments of the chain by LC-MS and were then quantified.
For the diagnosis of MPS II, HS was depolymerized by the bacterial
enzyme heparin lyase, releasing the non-reducing end disaccharide
2-sulfoiduronic acid-N-sulfoglucosamine-6-sulfate (35) along with unsat-
urated disaccharides from internal cleavage (e.g., 36, Scheme 6).148 The
digestion products were derivatized with isotope-labeled aniline by reduc-
tive amination to facilitate improved LC resolution and quantification of
recovery with available standards. The non-reducing end biomarker (37)
for MPS II was readily distinguished from internal disaccharides (38) by its
greater mass in the LC-MS/MS.148
De Ruijter et al. also reported a similar assay to analyze levels of HS- and
DS-derived disaccharides in newborn DBS.149 The DBS were enzymati-
cally treated using heparinase I, II, III and chondroitinase B to liberate disac-
charides that were then quantified by LC-MS/MS. D0A0,150 the most
abundant disaccharide in HS, and D0a4, which makes up 94% of DS, were
the only two disaccharides that could be detected. The levels of both disac-
charides were significantly elevated in MPS patients compared with con-
trols, although the method is not specific for MPS II. Similarly, various
other assays have been described that depolymerize HS into disaccharides,
for example, by methanolysis151–154 or butanolysis155,156 degradation.
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Currently, there are two recombinant IDS enzymes available for ERT for
MPS II patients: idursulfase (Elaprase®)160 or idursulfase beta (Hunterase®).161
Both idursulfase and idursulfase beta are derived from the human IDS gene via
recombinant DNA technology and thus have identical amino acid sequences.
However, idursulfase is produced from an HT-1080 cell line, while
idursulfase beta is produced from a CHO cell line. This accounts for some
differences in their post-translational modifications, such as formylglycine
content, which results in differences in specific enzyme activity. The enzymes
are heavily glycosylated with mannose-6-phosphate (M6P) and sialylated gly-
cans. The former allows selective binding to M6P receptors on the surface of
the cells, resulting in subsequent cellular internalization. The levels of M6P
and sialic acid are similar in both products but there is a difference in their
cellular uptake.161 A recent comparative study indicated that idursulfase beta
contained less high-mannose type and hybrid-type glycans compared with
idursulfase, which could account for its lower immunogenicity.162
ERT has been shown to benefit a majority of individuals with MPS II by
reducing urinary GAG excretion levels, decreasing the volumes of their liver
and spleen, and increasing their cardiopulmonary function and average
walking distance.8,160,163,164 ERT with idursulfase or idursulfase beta is gen-
erally well tolerated, and the adverse infusion-related events that commonly
occur during therapy can be easily managed by the temporary pausing of infu-
sion, or by providing antihistamines and/or steroid medications before subse-
quent infusions.163,164 However, ERT is not a cure and has several limitations.
ERT using idursulfase is an expensive therapy with an estimated average cost
of US$490,000 in a 30 kg child.163 Moreover, the recombinant enzyme
does not cross the blood–brain barrier (BBB) and hence does not alter the pro-
gression of CNS disease among severely affected patients.27 In order to address
the issues with lack of BBB penetration, ERT with delivery by the intrathecal
or intracerebroventricular route is being investigated in several clinical trials.165
Another approach under investigation is the development of IDS-fusion
proteins specifically engineered to cross the BBB. For example, AGT-182 is
a fusion protein containing IDS and an anti-human insulin receptor mono-
clonal antibody (HIRMAb).166 The HIRMAb domain of the fusion protein
acts as a molecular Trojan horse to ferry the fused IDS across the BBB
via receptor-mediated transport on the insulin receptor, and across the cell
plasma membrane by receptor-mediated endocytosis. Brain uptake of AGT-
182 as well as safety and pharmacokinetics were demonstrated in Rhesus
monkeys following intravenous administration.166,167 JR-141 is another
fusion protein that consists of an IDS enzyme linked to an anti-transferrin
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receptor antibody. It has been reported to cross the BBB, reduce GAG accu-
mulation in the brain, and maintain cognitive functions in the MPS II
mouse model.168 Both AGT-182 and JR-141 are undergoing clinical
evaluation.165
Fig. 6 Structures of compounds evaluated for substrate reduction therapy for MPS
disorders.
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Fig. 7 Structures of pharmacological chaperone DS20 (42) and multivalent IDS inhibi-
tors with putative pharmacological chaperone activity (43–45).
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When D2S0 was incubated with recombinant IDS in vitro, it enhanced the
stability of the enzyme toward thermal degradation in a dose-dependent
manner. In addition, D2S0 increased the residual activity of IDS in MPS II
patient fibroblasts and in HEK293T cells expressing mutated IDS. Cardona
and co-workers synthesized a nonavalent trihydroxypiperidine dendrimer
43 as a glycosidase inhibitor. Interestingly, 43 was also evaluated against
IDS and found to have modest inhibitory activity (69% at 1 mM),186
thus identifying it as a potential PC for MPS II. Replacement of the piper-
idine core of the dendrimer with a pyrrolidine resulted in more potent
inhibitors 44 (IC50 ¼ 140 μM) and 45 (IC50 ¼ 31 μM).187 Multivalent pre-
sentation of the same pyrrolidine as in 44 onto gold nanoparticles resulted
in a poor inhibitor for IDS,188 although it did show good inhibition of
N-acetylgalactosamine-6-sulfatase, whose deficiency leads to MPS IVA.
The evaluation of the chaperone activity of these compounds for IDS
has yet not been reported.
however, clinical trials are either in progress or are scheduled, including for
MPS II (e.g., RGX-121 and SB-913).193 In preclinical studies, intracisternal
gene therapy with an adeno-associated virus serotype 9 (AAV9) vector
encoding murine IDS was reported to correct neurological and systemic
symptoms in MPS II mice.194 In other studies, an AAV9 vector carrying
the human IDS gene was administered to MPS II mice via the intra-
cerebroventricular route.195,196 The treatments showed reduced GAG accu-
mulation in the brain and improved neurological and behavioral responses in
the mice. These studies indicate that intra-CSF administration of AAV9
gene therapy should be useful for MPS II patients. RGX-121 is a gene ther-
apy product in clinical development that consists of an AAV9 vector con-
taining the human IDS gene administered by intrathecal injection.193
SB-913 contains a zinc finger nuclease (ZFN) in an AAV6 vector delivered
by intravenous infusion and is undergoing clinical trials.193 The ZFN is a
genetic engineering tool that modifies DNA sequences, mediating the
site-specific insertion of the corrective gene.
6. Conclusions
MPS II is a rare, inherited lysosomal storage disease caused by muta-
tions in the enzyme IDS. The function of IDS is to cleave the 2-O-sulfate
groups on terminal, non-reducing end IdoA residues on HS and DS in the
lysosome. Deficiency of IDS activity results in accumulation of HS and DS
in the lysosome leading to pathological changes in multiple organs. MPS II is
a progressive disease with a wide range of symptoms. Severely affected indi-
viduals have profound neurological impairment and a significantly short-
ened lifespan. An understanding of the function of IDS has led to
significant progress in the development of various assays, particularly those
based on LC-MS/MS, for enzyme activity or detecting the presence of bio-
markers for diagnosis/newborn screening and for monitoring of new ther-
apies. The current standard of care is ERT; however, the recombinant
enzyme does not cross the BBB and thus has little impact on neurological
symptoms. The past decade has seen significant progress toward the devel-
opment of new treatment options, and some of these have progressed to
clinical trials. These include efforts to develop IDS-fusion proteins specifi-
cally engineered to cross the BBB, small-molecule therapies based on sub-
strate reduction or pharmacological chaperones, and gene therapy
approaches, with the latter offering hope of a one-time permanent treat-
ment. Continued research and the combination of multiple effective
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therapies with early diagnosis could result in improved prospects for MPS II
patients in the future.
Acknowledgments
We thank the University of Queensland, the National MPS Society (USA), and the
Australian Research Council (DP170104431 to V.F.) for financial support.
Abbreviations
AAV adeno-associated virus
anM 2,5-anhydro-D-mannitol
BBB blood–brain barrier
CID collision-induced dissociation
CNS central nervous system
CS chondroitin sulfate
CSF cerebrospinal fluid
DBS dried blood spot
DNA deoxyribonucleic acid
DS dermatan sulfate
ERT enzyme replacement therapy
ESI-MS/MS electrospray ionization tandem mass spectrometry
FGly α-formylglycine
GAG glycosaminoglycan
HIRMAb human insulin receptor monoclonal antibody
HPLC high performance liquid chromatography
HPLC-MS/MS high performance liquid chromatography-tandem mass spectrometry
HS heparan sulfate
HSCT hematopoietic stem-cell transplant
IdoA L-iduronic acid
IDS iduronate-2-sulfatase
KS keratan sulfate
LC liquid chromatography
LC-MS/MS liquid chromatography-tandem mass spectrometry
LSD lysosomal storage disease
M6P mannose-6-phosphate
MPS mucopolysaccharidosis
MS/MS tandem mass spectrometry
MU 4-methylumbelliferyl
NBS newborn screening
PC pharmacological chaperone
PCT pharmacological chaperone therapy
SRT substrate reduction therapy
UPLC ultra-performance liquid chromatography
UPLC-MS/MS ultra-performance liquid chromatography-tandem mass spectrometry
ZFN zinc finger nuclease
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