Review of the use of idursulfase in the treatment of mucopolysaccharidosis II.

Abstract

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a heterogeneous, progressive X-linked recessively inherited lysosomal storage disease that is caused by a deficiency of the enzyme iduronate-2-sulfatase, resulting in abnormal tissue accumulation of the glycosaminoglycans, dermatan sulfate and heparan sulfate. The disorder results from mutations in IDS, which is located at Xq28. Over 300 pathogenic mutations have been identified to date. The management of MPS II requires multidisciplinary care because of the many affected organ systems. Replacement of functional enzyme to involved tissues has been a focus of various therapies for several decades. The transplantation of hematopoietic stem cells provides enzymatic reconstitution in many target tissues, but the clinical response has been disappointing. Recently, enzyme replacement therapy with recombinant human iduronate-2-sulfatase (idursulfase, Elaprase((R)); Shire HGT Pharmaceuticals, Cambridge MA, USA), was approved by the in the US and Europe as a safe and effective treatment for individuals with MPS II. This review presents a comprehensive overview of MPS II and summarizes the recent literature on therapy for the disease.

Full text

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© 2008 Dove Medical Press Limited. All rights reserved
Biologics: Targets & Therapy 2008:2(2) 311–320
311
R E V I E W
Review of the use of idursulfase in the treatment
of mucopolysaccharidosis II
T Andrew Burrow
Nancy D Leslie
The Division of Human Genetics,
Cincinnati Children’s Hospital Medical
Center, and the Department of
Pediatrics, University of Cincinnati
College of Medicine, Cincinnati,
OH, USA
Correspondence: Nancy D Leslie
Cincinnati Children’s Hospital Medical
Center, Division of Human Genetics, 3333
Burnet Avenue, MLC 4006, Cincinnati,
OH 45229-3039, USA
Tel +1 513 636 4760
Fax +1 513 636 7297
Email nancy.leslie@CCHMC.org
Abstract: Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a heterogeneous,
progressive X-linked recessively inherited lysosomal storage disease that is caused by a defi -
ciency of the enzyme iduronate-2-sulfatase, resulting in abnormal tissue accumulation of the
glycosaminoglycans, dermatan sulfate and heparan sulfate. The disorder results from muta-
tions in IDS, which is located at Xq28. Over 300 pathogenic mutations have been identifi ed to
date. The management of MPS II requires multidisciplinary care because of the many affected
organ systems. Replacement of functional enzyme to involved tissues has been a focus of vari-
ous therapies for several decades. The transplantation of hematopoietic stem cells provides
enzymatic reconstitution in many target tissues, but the clinical response has been disappoint-
ing. Recently, enzyme replacement therapy with recombinant human iduronate-2-sulfatase
(idursulfase, Elaprase®; Shire HGT Pharmaceuticals, Cambridge MA, USA), was approved by
the in the US and Europe as a safe and effective treatment for individuals with MPS II. This
review presents a comprehensive overview of MPS II and summarizes the recent literature on
therapy for the disease.
Keywords: mucopolysaccharidosis type II, Hunter syndrome, enzyme replacement therapy
Introduction
The mucopolysaccharidoses are a group of lysosomal storage diseases characterized
by a defi ciency of enzymes responsible for the stepwise degradation of glycosamino-
glycans. With the exception of mucopolysaccharidosis type II (MPS II; Hunter syn-
drome), an X-linked recessively inherited disorder, all are inherited in an autosomal
recessive manner. MPS II is a heterogeneous, progressive lysosomal storage disease
that results from defi ciency of the enzyme, iduronate-2-sulfatase, which cleaves an
O-linked sulfate from dermatan sulfate and heparan sulfate (Neufeld and Muenzer
2001). Consequently, dermatan sulfate and heparan sulfate progressively accumulate
in the lysosomes, leading to the phenotypic features observed in the disease. The
disease occurs with an incidence of approximately 1.3 cases per 100,000 male live
births in Germany and the Netherlands (Poorthuis et al 1999; Baehner et al 2005).
Approximately two-thirds of cases exhibit central nervous system (CNS) involvement,
representing more severe phenotypes of the disease (Wraith et al 2007, 2008). A few
affected females have also been reported, often in association with extremely skewed
X-inactivation (Tuschl et al 2005). The disorder results from mutations in IDS, which
is located at Xq28. Over 300 mutations have been identifi ed to date, many of which
are private and associated with a signifi cant new mutation rate in the male genome
(Froissart et al 2007).
Hematopoietic stem cell transplantation (HSCT) has been performed in numerous
individuals with varying degrees of severity of MPS II, but limited success and signifi -
cant risk. Enzyme replacement therapy (ERT) involves the intravenous administration
of a purifi ed, carbohydrate-modifi ed, recombinant human enzyme into individuals in

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Burrow and Leslie
whom the enzyme is missing or defective. The recombinant
enzyme undergoes receptor mediated cell uptake and sub-
sequent intracellular traffi cking into the lysosomes, where
it carries out its specifi c function. ERT has been used suc-
cessfully for the primary treatment of Gaucher disease, Fabry
disease, and mucopolysaccharidosis types I and VI. Recom-
binant iduronate-2-sulfatase (idursulfase, Elaprase®; Shire
HGT Pharmaceuticals, Cambridge, MA, USA) was approved
in July, 2006 in the US and January, 2007 in Europe as a safe
and effective treatment for individuals with MPS II.
This review presents a comprehensive overview of MPS
II and summarizes the recent literature on therapy, specifi -
cally ERT, for the disease.
Clinical features
Two clinical forms of MPS II have been historically rec-
ognized, attenuated and severe, which were primarily dis-
tinguished by the presence of CNS involvement. However,
MPS II is more appropriately considered a heterogeneous
disorder with a broad spectrum of clinical features. Even
individuals with attenuated phenotypes of the disease may
experience significant morbidity and limitation of life
expectancy.
Individuals with attenuated phenotypes of MPS II do
not exhibit CNS impairment. A signifi cant body of work
prepared by Young and Harper in the 1980s reported a
mean age of recognition of symptoms of 4.3 years, the most
common presenting feature being coarse facial appearance
(Young and Harper 1982; Young et al 1982). More recently,
Schwartz and colleagues reported a median age of recognition
of symptoms of 3.25 years in their patients with attenuated
disease (Schwartz et al 2007). Despite reported mean ages
of death from 17 to 21.7 years in this population, survival
well into adulthood is not unexpected (Young and Harper
1982; Young et al 1982; Schwartz et al 2007). Conversely,
individuals with severe MPS II demonstrate clinically
signifi cant and progressive CNS involvement. Symptoms
associated with severe MPS II are usually recognized earlier
than those the attenuated phenotype. In the earlier reviews,
Young and Harper reported a mean age of recognition of
symptoms of approximately 2.47 years, the most common
presenting feature being developmental delay. The median
age of recognition of symptoms reported by Schwartz and
colleagues was only slightly earlier at 2 years (Young et al
1982; Young and Harper 1983; Schwartz et al 2007). Lifes-
pan in these patients is considerably shortened, commonly
as a result of pulmonary and/or cardiac disease (Young et al
1982; Young and Harper 1983). The mean ages of death from
11.8 to 14.6 years have not changed much in 20 years (Young
and Harper 1983; Schwartz et al 2007).
Macrocephaly is a common fi nding, often becoming more
apparent with age (Young et al 1982). Facial features include
progressive coarsening, with frontal bossing, prominent
supraorbital ridge, large nose and fl at nasal bridge, widely
spaced teeth, thickened gingival mucosa, and macroglos-
sia, The body habitus is typically broadly built with a short
neck, broad chest, and protuberant abdomen (Young and
Harper 1982, 1983; Young et al 1982). The skin is thick and
hirsutism is common. Individuals may exhibit numerous
Mongolian spots. Skin-colored papules and nodules (some-
times termed peau d’orange) may be observed, particularly
on the back, upper arms, shoulders, and thighs, and among
the MPS disorders, this fi nding is considered characteristic
for Hunter syndrome.
Early linear growth is typically normal to advanced, which
may limit recognition of the disease. The widely recognized
short stature with contractures develops relatively late when
compared to features such as hepatosplenomegaly, airway
disease, and developmental delays. Additionally, patients
may initially be overweight for age and height (Figure 1).
Corneal clouding, which is observed in other forms
mucopolysaccharidosis, is characteristically absent in MPS
II. Refraction errors are frequently identifi ed on ophthalmo-
logic examination (Schwartz et al 2007). Progressive retinal
degeneration and optic nerve disease may be observed,
particularly in severely affected individuals. Papilledema
may be noted these patients, even in the absence of elevated
intracranial pressure, possibly a result of glycosaminoglycan
accumulation within the sclera resulting in compression of
the optic nerve at the intersceral level (Young and Harper
1982; Beck and Cole 1984; Neufeld and Muenzer 2001).
Progressive, mixed conductive and sensorineural hearing
loss begins in early childhood. The conductive component
results from eustachian tube dysfunction, thick middle ear
effusion, and effects of chronic otitis media (Young and
Harper 1982; Young et al 1982; Young and Harper 1983;
Neufeld and Muenzer 2001).
Chronic nasal discharge and frequent upper respira-
tory tract infections are common fi ndings in these patients.
Progressive deposition of glycosaminoglycans in the larynx
results in a characteristically hoarse, low pitched voice. Pro-
gressive accumulation of glycosaminoglycans in supraglottic
tissue, tongue, tonsils, and adenoids, produces muffl ing of the
voice, and places individuals at a signifi cant risk of airway
obstruction, particularly during sleep and perioperatively.
Obstructive sleep apnea is a considerable problem for many

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Idursulfase in treatment of MPS II
individuals, many of whom ultimately require some form
of therapeutic intervention, including tonsillectomy and/or
adenoidectomy, positive pressure ventilation, or trache-
ostomy. Lower respiratory illnesses are more common in
severely affected individuals and become progressively more
severe and life threatening as the individual’s disease wors-
ens and comorbidities arise. Additionally, rib cage rigidity
and abdominal distension diminish chest excursion, further
contributing to pulmonary insuffi ciency (Young and Harper
1982, 1983; Young et al 1982).
SOURCE: Developed by the National Center for Health Statistics in collaboration with
the National Center for Chronic Disease Prevention and Health Promotion (2000).
http://www.cdc.gov/growthcharts
Published May 30, 2000 (modified 11/21/00).
2 to 20 years: Boys
Stature-for -age and Weight-for-age percentiles
NAME
Mother’s Stature
Date
Father’s Stature
Weight AgeStature BMI*
*To Calculate BMI: Weight (kg) + Stature (cm) + stature (cm) x 100,000
or Weight (lb) + Sature (in) + sature (in) x 703
in
cm
345
in
76
S
T
A
T
U
R
E
S
T
A
T
U
R
E
W
E
I
G
H
T
W
E
I
G
H
T
cm
58
lb
lb
AGE (YEARS)
AGE (YEARS)
35
30
25
20
15
10
kg
35
40
55
60
65
45
50
30
25
20
15
10
kg
30
40
50
60
70
80
80
115
120
140
145
160
12
19 20
72
70
68
66
64
62
210
200
190
180
130
100
80
70
60
70
75
80
85
100
105
90
95
30
23456789 10 1113 1417 18 201915
SAFER - HEALTHIER - PEOPLE*
16 12
50
40
90
110
120
140
150
160
170
220
230
60
74
95
90
75
50
25
10
5
95
90
75
50
25
10
5
190
185
180
175
170
67910 118
165
160
155
150
18
17
16 1514 13
155
150
135
130
125
110
105
100
95
90
85
30
32
34
36
38
40
42
44
46
48
50
52
54
56
60
62
RECORD #
Figure 1 Growth chart demonstrating the typical growth pattern in patients with Hunter syndrome.

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Biologics: Targets & Therapy 2008:2(2)
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Burrow and Leslie
Cardiac disease presents a common source of morbidity
and mortality in these patients. Accumulation of glycosami-
noglycans within the cardiac valves (specifi cally mitral and
aortic valves) results in thickening and abnormal function
of the valves and impaired cardiac function. Cardiac valve
replacement has been performed in these patients with suc-
cess (Dangel 1998; Bhattacharya et al 2005). Additionally,
progressive left ventricular hypertrophy/interventricular
septal thickening may further lead to impaired cardiac func-
tion (Dangel 1998; Mohan et al 2002).
Hepatosplenomegaly is a consistent feature in MPS II.
Umbilical and inguinal hernias are frequent, and may recur after
surgery. Chronic diarrhea is commonly reported in severely
affected individuals, and may be one of the most distressing
features of the disease (Young and Harper 1983). Its etiology is
unclear; however, this symptom may be the result of impaired
autonomic innervation of the intestines (Elsner 1970).
Skeletal radiographs may demonstrate dysostosis mul-
tiplex, which is characterized by macrocephaly, thickened
calvarium, and J-shaped sella. The chest demonstrates
wide, oar shaped ribs, and short, thickened clavicles. The
spine shows anterior beaking of the lumbar vertebrae. The
pelvis demonstrates wide, fl ared ilia, dysplastic acetabulae,
small, fl attened femoral heads, and coxa valga. The tubular
bones exhibit thickened cortices, irregular metaphyses, and
poorly developed epiphyseal centers. The phalanges are also
shortened and trapezoidal in shape (Figure 2) (Spranger et al
2002). Skeletal abnormalities also affect the jaw, leading to
limited range of motion.
A progressive, destructive arthropathy may affect all the
joints, particularly the hips, eventually leading to decreased
range of motion and signifi cant disability. Physical therapy
may provide some benefi t in preserving joint function (Wraith
et al 2008); however, surgical intervention may eventually
be required to stabilize and/or repair the damaged joints.
Progressive joint contractures may be quite debilitating.
Contractures of the hands, eventually give rise to a claw-like
hand deformity. Carpal tunnel syndrome is a common, albeit
frequently overlooked manifestation that may become quite
severe, ultimately requiring surgical intervention (Haddad
et al 1997). Progressive motor impairment into early adult-
hood has been documented using Functional Independence
Measures (Kato et al 2007).
Progressive neurologic deterioration characterizes the
severe phenotypes of MPS II with slow global acquisition
of developmental milestones during the preschool years.
Behavior problems, particularly aggressiveness and hyper-
activity, may be signifi cant and quite taxing on care givers
(Young and Harper 1981). A plateau occurs around age 6,
followed by progressive neurological deterioration. In the
late stages of the disease, individuals are severely impaired
and dependent upon caregivers for all their needs (Young and
Harper 1983). Pyramidal tract disease, ie increased muscle
tone, exaggerated deep tendon refl exes, and ankle clonus has
been observed (Young and Harper, 1982, 1983; Young et al
1982). Seizure activity, reported in 18% of individuals in the
Hunter Outcome Survey (HOS) registry (Wraith et al 2007)
appears in the fi rst decade of life, and is usually amenable
to antiepileptic therapy. Communicating hydrocephalus
may develop during the end of fi rst decade of life, further
contributing to the neurologic deterioration (Neufeld and
Muenzer 2001).
In individuals with attenuated disease, cognitive dete-
rioration does not occur and the prevalence of neurologic
manifestations is decreased compared to severely affected
individuals. Nonetheless, abnormal MRI fi ndings, including
volume loss and white matter lesions, are seen in individuals
with the attenuated form (Parsons et al 1996). Individuals are
expected to have normal intelligence to mild delays. How-
ever, certain medical comorbities, ie, deafness and decreased
joint mobility, may contribute to problems in school. The
behavioral problems observed in severely affected individu-
als do not occur; however, these individuals may have psy-
chological problems related to their medical comorbidities
and adjustment to their disease (Young and Harper 1981).
Figure 2 X-ray of the hand demonstrating the typical radiographic fi ndings in patients
with Hunter syndrome. The small density over the proximal hypothenar eminence in
this image represents a foreign body.

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Idursulfase in treatment of MPS II
Spinal cord compression is one of the most serious
complications of MPS II, and can lead to permanent neuro-
logic damage or death, if not detected and treated early. This
may result from foramen magnum and vertebral canal ste-
nosis, meningeal thickening from glycosaminoglycan accu-
mulation, and less commonly from atlanto-axial subluxation
(Parsons et al 1996; O’Brien et al 1997).
The work of Young and Harper (Young and Harper 1981,
1982, 1983; Young et al 1982) and others has contributed
signifi cantly to our understanding of the clinical features of
MPS II. However, these studies were conducted prior to the
availability of modern supportive and defi nitive medical care.
Comprehensive studies addressing the effectiveness of newer
medical techniques in treating patients with MPS II are only
beginning to appear in the literature. It is anticipated that
rare disease registries such as the Hunter Outcome Survey,
sponsored by Shire HGT Pharmaceuticals, will provide an
opportunity to assess both the natural history and effect of
interventions on patients currently cared for in participating
centers. Preliminary fi ndings from the HOS as well as a
similar review of the clinical manifestations and treatment
of MPS II were recently reported by Wraith and colleagues
(Wraith et al 2008).
Molecular
Iduronate-2-sulfatase, a member of the sulfatase family,
catalyzes the removal of the sulfate group from the
2- position of L-iduronic acid in dermatan sulfate and
heparan sulfate in lysosomes (Neufeld and Muenzer 2001).
IDS, which is located at Xq28, spans approximately 24 kb,
consists of 9 exons and 8 introns, and has a coding sequence
of 2.3 kb. A pseudogene, IDS2, located approximately
20 kb distal to the gene, contains sequences homologous to
exon II, exon III, intron 2, and a chimeric intron3-intron7
(Froissart et al 2002). Its exact function is unclear; how-
ever, pathogenic structural rearrangements between IDS2
and IDS have been identifi ed in individuals with MPS
II. Sequence analysis of human IDS cDNA predicts the
translation of a 550 amino acid precursor peptide, includ-
ing a 25 amino acid amino-terminal signal sequence and
eight additional amino acids that are removed from the
proprotein (Wilson et al 1990).
IDS has a strong sequence homology to other human
sulfatases, including arylsulfatases A, B, and C, and
glucosamine-6-sulfatase (Wilson et al 1990). All members
of the sulfatase family undergo post-translational modifi ca-
tion in the endoplasmic reticulum during which a conserved
cysteine residue located within the active site is converted
into Cα-formylglycine by formylglycine-generating enzyme
(FGE). Cα-formylglycine is essential for catalytic activity
of the sulfatases. Mutations in SUMF1, which codes for
FGE, results in severely reduced activity of the sulfatases,
leading to multiple sulfatase defi ciency, an autosomal reces-
sive disorder, the phenotype of which combines features of
disorders resulting from individual sulfatase defi ciencies
(Dierks et al 2003).
The Human Gene Mutation Database (HGMD) pres-
ently documents 345 disease causing mutations in IDS
(Krawczak and Cooper 1997; Stenson et al 2003), many of
which are private. They include missense, nonsense, splice
site mutations, small insertions and deletions, partial and
whole gene deletions, and large rearrangements (Stenson
et al 2003). Approximately 12% of cases arise de novo
from maternal meiosis (Rathmann et al 1996; Vafi adaki
et al 1998). Approximately 80% of all cases of MPS II result
from small deletions, insertions, or single base substitutions,
while the remaining 20% of cases result from large scale
deletions in IDS or structural rearrangements (Hopwood
et al 1993; Froissart et al 2007). Point mutations account for
approximately 50% of all mutations, and tend occur more
frequently in exons III, VIII, and IX, particularly at CpG
sites (Rathmann et al 1996).
The identifi cation of genotype-phenotype correlations in
MPS II has been challenging for several reasons. Measured
IDS activity in plasma or circulating cells does not differ-
entiate between severe or attenuated forms, suggesting that
the differences in disease threshold fall below the range of
measurable enzyme activity. There is currently no standard-
ized severity scoring system, although these tools are being
developed as therapeutic options are brought into clinical
application. There is broad degree of genotypic heterogene-
ity, and a signifi cant number of private mutations exist in this
disease (Froissart et al 2002, 2007). Despite these limitations,
certain genotype/phenotype correlations have been described.
Large gene alterations (deletions and rearrangements) are
typically associated with severe disease phenotypes because
of a complete absence of functional enzyme. Other genes,
including FMR-1 may also be deleted, further contributing
to the severe phenotypes, particularly development of mental
retardation (Froissart et al 2007).
Splice site mutations affecting consensus sequences,
small deletions or insertions causing frameshifts, and non-
sense mutations are generally associated with intermediate
and severe phenotypes (Hopwood et al 1993; Froissart
et al 1998, 2002; Vafi adaki et al 1998). However, there are
exceptions: The nonsense mutation Q513X is associated

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Burrow and Leslie
with an attenuated phenotype because the encoded amino
acid product lacks 19 C-terminal amino acids normally
removed during protein maturation (Froissart et al 2002).
The effects of splice site mutations are variable, depending
on the location and nature of the mutation and presence of
normal transcripts. Affected individuals may produce the
normal gene transcript in suffi cient, albeit low, levels to
avoid developing a severe phenotype.
The effects of missense mutations and small in-frame
deletions and insertions are often diffi cult to predict, and
expression studies are sometimes needed to differentiate a
polymorphism from a disease-causing mutation (Froissart
et al 2002). Missense mutations that do not signifi cantly
impact protein folding and/or enzyme activity are predicted
to result in attenuated phenotypes. Conversely, missense
mutations affecting sequences highly conserved among the
sulfatases generally result in a severe disease phenotype
(Froissart et al 1998).
Animal studies
A knockout mouse model of MPS II (ids y/-) has been devel-
oped by replacing exon 4 and a portion of exon 5 of IDS with
the neomycin resistance gene (Muenzer et al 2002; Garcia
et al 2007b). Affected mice exhibit many of the features
observed in humans, including elevated urine glycosami-
noglycan excretion, accumulation of glycosaminoglycans
in tissues and organs, and defi cient iduronate-2-sulfatase
enzyme activity. Clinical features include hepatospleno-
megaly, progressive skeletal abnormalities, and premature
death (Garcia et al 2007b).
Garcia and colleagues studied the effects of idursulfase
on the IdS-KO (ids y/-) mouse model (Garcia et al 2007a).
Idursulfase infused at various doses (0.1, 0.25, 0.5, and
1.0 mg/kg) and dosing frequencies (once, weekly, every
other week, and monthly), resulted in a reduction in urine
and tissue glycosaminoglycan levels. Additionally, liver
weight was signifi cantly reduced after 24 weeks of therapy
in mice treated with 1 mg idursulfase weekly and every other
week. This study provided further proof of the principle that
some histological and biochemical features of MPS II can be
effectively reversed with enzyme replacement therapy.
A gene therapy technique using the AAV2/8 vector
to selectively deliver human IDS cDNA to the liver in
the ids y/- mouse model resulted in a restoration of plasma and
tissue IDS activity in the treated mice (Cardone et al 2006).
Consequently, normalization of urine glycosaminoglycan
levels and clearance of glycosaminoglycan accumulation
within the visceral tissues was observed. Corrections of the
skeletal and locomotor defects were also observed in treated
mice. Interestingly, partial clearance of glycosaminoglycans
and improved IDS activity in the CNS were also reported,
including uptake of human IDS into the lysosomes of the
cortex and cerebellum. These results suggest that signifi -
cant overexpression of IDS in peripheral (liver) tissue may
allow penetration of IDS at low levels past the blood brain
barrier.
Friso and colleagues (Friso et al 2005) evaluated an
alternate delivery system by intraperitoneally implanting
alginate microcapsules containing C2C12 murine myoblasts
overexpressing IDS into ids y/- mice. Detectable levels of
IDS in plasma and tissues of implanted ids y/- mice were
found at 3 days and 2 weeks, respectively and persisting at
8 weeks of therapy. Urine glycosaminoglycan excretion was
signifi cantly decreased in implanted knockout mice between
weeks 4 and 6 of therapy. Additionally, a signifi cant decrease
in tissue glycosaminoglycan accumulation was noted bio-
chemically in the kidney and spleen after 8 weeks of therapy.
Decreased tissue glycosaminoglycan accumulation was also
apparent histologically in the liver, spleen, and kidney after
8 weeks of therapy.
Therapy
The management of MPS II requires lifelong attention to the
multisystemic involvement by a team of specialists experi-
enced in the management of this disease since none of the
therapeutic options currently available result in complete
resolution of morbidity.
HSCT has been successful in improving certain disease
manifestations in patients with mucopolysaccharidosis type I
(MPS I, Hurler syndrome), including visceral manifestations
and attenuation of neurologic disease progression when per-
formed early (ie, less than 2 years of age), and is considered
a mainstay in the treatment of severe MPS I. HSCT has been
performed in numerous individuals with MPS II. In some
cases, individuals demonstrate improvement of the visceral
and skeletal manifestations of the disease, ie, decreased
urine glycosaminoglycan excretion, decreased liver and
spleen volumes, diminished facial coarsening, improved
respiratory function, and increased joint mobility (Coppa
et al 1995; McKinnis et al 1996; Mullen et al 2000; Froissart
et al 2002). However, HSCT does not appear to mitigate the
progressive neurodegenerative disease often present in MPS
II (Coppa et al 1995; Shapiro et al 1995; McKinnis et al 1996;
Vellodi et al 1999). Additionally, this technique is associated
with a signifi cant risk of morbidity and mortality. For these
reasons, and with the advent of enzyme replacement therapy

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Idursulfase in treatment of MPS II
(discussed below), HSCT has limited, if any, utility in the
treatment of MPS II.
Elaprase® (idursulfase; Shire HGT Pharmaceuticals,
Cambridge, MA) was approved in the US in July, 2006 and
Europe in January, 2007 for the treatment of individuals
with MPS II at a recommended dose of 0.5 mg/kg admin-
istered once weekly as an intravenous infusion. Idursulfase
is a purifi ed form of iduronate-2-sulfatase produced in a
human cell line via recombinant DNA technology. The 525
amino acid glycoprotein contains 8 N-linked glycosylation
sites that are occupied by 2 bis mannose-6-phosphate
containing oligosaccharide chains (Muenzer et al 2006).
These mannose-6-phosphate (M6P) chains bind to M6P
receptors on the cell surface, allowing for subsequent
internalization and traffi cking to the lysosomes, where
the enzyme is catalytically active. The enzyme activity
of idursulfase is dependent upon the post-translational
modifi cation of cysteine to Cα-formylglycine within the
enzyme’s active site. This modifi cation was demonstrated
in 50% of the molecules of idursulfase (Muenzer et al
2006). Idursulfase also contains complex, highly sialylated
glycans that prolong the circulating half-life of the drug
(Muenzer et al 2006).
The safety and effi cacy of idursulfase was evaluated in
a randomized, double-blinded, placebo controlled phase I/II
clinical trial (Muenzer et al 2007). In this study, 12 partici-
pants, between the ages of 6 and 20, who met clinical and
biochemical criteria for MPS II and were able to cooperate
with all study procedures (which excluded severely affected
MPS II patients), received idursulfase at doses of 0.15, 0.5,
or 1.5 mg/kg or placebo infused once per week over a period
of 24 weeks, followed by a 6-month open-label extension
study in which all participants received idursulfase. Clinical
endpoints were evaluated after 48 weeks of therapy with
active agent and compared with the three patients observed
over 24 weeks of placebo infusions.
Urine glycosaminoglycan excretion was reduced within
2 weeks of initiating idursulfase, and continued to be sig-
nifi cantly reduced after 48 weeks of therapy (p ? 0.0001). A
majority of patients experienced reductions of urine GAGs
to near normal levels, while two individuals achieved urine
GAGs within the normal range after 6 months. Liver and
spleen volumes were signifi cantly decreased in the pooled
study population after 24 and 48 weeks of therapy (p ? 0.01
and p ? 0.001, respectively). Sixty-six percent of individuals
with baseline hepatomegaly and all individuals with baseline
splenomegaly experienced a normalization of organ volumes.
Finally, after 48 weeks of therapy, average walking distance
of the combined groups increased by an average of 48 m
(p = 0.013).
In a follow-up phase II/III clinical study, the safety and
effi cacy of idursulfase was evaluated in 96 patients, ages
5–31, with MPS II (Muenzer et al 2006). In this study design,
patients were randomized to receive placebo or idursulfase
0.5 mg/kg weekly or every other week, for 53 weeks, fol-
lowed by an open-label extension. Participants met clinical
and biochemical criteria for MPS II, were able to cooperate
with all study procedures (excluding severely affected MPS
II patients), and had a baseline forced vital capacity (FVC)
less than 80% of predicted. The primary endpoint of the
study was a 2-component composite score of %FVC and
the 6-minute walk test.
After 53 weeks of therapy, patients in the weekly and
every other week idursulfase groups exhibited signifi cant
improvement in the 2-component composite endpoint com-
pared to placebo (p = 0.0049 and p = 0.0416, respectively).
However, there was no difference between the two idursul-
fase treatment groups. The weekly idursulfase treatment
group experienced a 37 m increase in distance walked in
the 6-minute walk test (P = 0.013) compared to placebo.
Additionally, the weekly idursulfase treatment group expe-
rienced a 2.7% increase in predicted %FVC (p = 0.065) and
a 160 mL increase in absolute FVC (p = 0.001) compared
to placebo at 53 weeks.
After 53 weeks of therapy, urine glycosaminoglycan lev-
els were signifi cantly decreased in both idursulfase treatment
groups compared to placebo (p ? 0.0001). After 53 weeks of
therapy, 40.6% of individuals in both idursulfase treatment
groups experienced normalization of urine GAG levels, while
urine GAG levels approached the upper end of normal in a
majority of the remaining patients treated with idursulfase.
Liver and spleen volumes diminished signifi cantly from
baseline in both idursulfase treatment groups, compared with
placebo (p ? 0.0001). Approximately 80% of individuals
with baseline hepatomegaly who received treatment with
idursulfase (weekly and every other week) had normal liver
volumes after 18 and 53 weeks of therapy.
Idursulfase was generally well tolerated in the phase
I/II and phase II/III clinical trials. The most frequently
reported adverse events included fever, headache, cough,
pharyngitis, upper respiratory tract infection, nasal conges-
tion, nausea, vomiting, abdominal pain, and diarrhea. Of the
adverse events considered possibly related to idursulfase
therapy, infusion-related events were the most common. The
incidence of infusion-related events was greatest between
weeks 4 and 12 and decreased subsequently. These events

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Burrow and Leslie
were generally managed by stopping the initial infusion and
premedicating with antihistamines and/or corticosteroids
prior to subsequent infusions. If a reaction occurred during
subsequent infusions, the infusion was stopped and restarted
after the reaction resolved. Two deaths occurred during the
phase II/III study, neither of which was considered to be
related to idursulfase therapy.
IgG antibodies to idursulfase were detected in approxi-
mately 50% of patients, the highest prevalence of which
occurred after 27 weeks of therapy (44.4% of patients).
However, only 31.7% of patients in the idursulfase treatment
groups remained antibody positive after 53 weeks of therapy.
Although the presence of IgG anti-idursulfase antibodies
was associated with an approximately two thirds reduction
in urine glycosaminoglycan excretion in the phase II/III
clinical trial, there was reportedly no association between
the presence of antibodies and adverse events or clinical
assessments. IgE antibodies to idursulfase were not detected
in either study.
Patients receiving ERT should be monitored carefully
during the infusion and for a period afterwards for an infu-
sion related reaction to idursulfase. Additionally, easy access
to emergency equipment/medications by skilled providers
should be available. Initial infusion-related reactions are
usually managed by discontinuing the infusion and pro-
viding antihistamines and/or corticosteroids. Subsequent
infusions may be managed by slowing the infusion rate and
pre-treating with antihistamines and/or corticosteroids. If a
subsequent reaction occurs, the infusion should be stopped
and appropriate treatment provided. Depending upon the
severity of the reaction, the infusion may be restarted upon
resolution of the reaction.
Patients with compromised respiratory function or acute
respiratory disease may be at an increased risk of experienc-
ing a severe infusion-related reaction. Recently, two patients
experienced late-emergent anaphylactoid reactions approxi-
mately 24 hours after having experienced initial anaphylactic
reactions during enzyme infusions. Thus, prolonged obser-
vation times are indicated in certain populations (Elaprase®
package insert).
Idursulfase has been studied only in patients with attenu-
ated disease. Consequently, the effects of idursulfase on
CNS disease have not been formally evaluated. However,
idursulfase does not cross the blood–brain barrier; thus it is
not expected to have a signifi cant effect on the neurological
features of MPS II. Whether ERT should be offered to indi-
viduals with CNS manifestations is unclear. Wraith and col-
leagues suggest that patients with severe CNS manifestations
be offered ERT for a trial period of 12–18 months, after
which time a decision is made whether to continue with the
therapy (Wraith et al 2008).
Idursulfase has not been studied in patients younger than
5 years of age. Many patients under 5 years are currently
being treated and there is no reason to think that ERT would
be less effective for the visceral manifestations in these young
patients. Evaluation of the long term effi cacy and safety of
idursulfase in these populations are needed.
While ERT is expected to provide a benefi t to patients
receiving the therapy, it is not without a signifi cant fi nancial
and emotional burden. ERT using idursulfase is expensive,
with an estimated average annual cost of US$491,999.04 in
a 30 kg child, based upon the US average wholesale price
obtained from the Red Book Database (http://micromedex.
com/products/redbook/database/). However, the actual
cost of ERT will vary depending upon the individual’s
weight, and amount of drug prescribed. Additionally, other
fees, including a markup on the drug from the hospital,
private offi ce and infusion center, and for supplies may be
incurred. Insurance coverage may present a signifi cant issue
for patients. For example, premiums may become unaf-
fordable for individuals with private insurance coverage.
Additionally, the lifetime maximums in many policies will
be exceeded in several years given the expense of the drug
and other costs. Shire HGT Pharmaceuticals has developed a
Patient Assistance Program that offers assistance to qualifi ed
patients on a case by case basis, primarily based on fi nancial
need. Private organizations, eg, the National Organization
for Rare Disorders, also have programs to assist families
with fi nancial costs related to ERT and healthcare coverage
(Burrow et al 2007).
ERT infusions in a hospital/infusion center environment
frequently require patients and their families to take time off
of work/school to receive treatments, further contributing
to their emotional/fi nancial burden. In patients who have
previously tolerated infusions without reactions, or mild
reactions easily treated with antipyretics/antihistamines and/
or slowed infusion rates, transferring patients to receiving
infusions in the home setting is a plausible option (Wraith
et al 2008). However, this transition should be performed
with consideration given these patients’ complex medical
histories, the “black box warning” on the label, and recent
reports of late-emergent anaphylactoid reactions in patients
treated with idursulfase. In patients who are transitioned to
home infusions, a skilled home care nurse should be present
and easy access to emergency equipment/medications in case
of reactions should be available.

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Idursulfase in treatment of MPS II
Alternative methods aimed at directly targeting enzyme
to the CNS, ie, intrathecally, have been previously evalu-
ated in MPS I animal models (Dickson et al 2007). A study
evaluating the safety and effi cacy of intrathecal ERT in the
treatment of certain spinal cord manifestations of MPS I is
currently recruiting participants. Intrathecal trials of ERT
for MPS II are planned. However, the differences between
the cognitive and behavioral manifestations in MPS I and II,
and the difference in response to HSCT are reminders that a
therapy with effi cacy in one of the MPS disorders may have
different outcomes in another.
Newer treatment modalities, ie, pharmacological chaperone
and substrate reduction therapy, are being developed for patients
with other lysosomal storage diseases, including Gaucher
disease (Cox et al 2000; Elstein et al 2004; Yu et al 2007a, b).
Pharmacological chaperone therapy is a therapeutic approach
in which small molecules selectively bind to and stabilize the
structure of target proteins in cells, allowing for improved
folding and traffi cking to the lysosomes and increased protein
activity. Substrate reduction therapy is a therapeutic approach
in which in which a pharmacologic agent decreases the produc-
tion of the molecule that typically accumulates within the cells
in individuals with a lysosomal storage disease so that the
patient’s residual enzyme may catabolize the accumulated
material. There are no current clinical trials examining these
therapies in MPS II, and the prospects for chaperone therapy
are low if there is no residual enzyme to protect.
Gene therapy offers signifi cant potential for the treat-
ment/cure of genetic diseases such as MPS II and several
attempts to express iduronate sulfatase through gene therapy
approaches have been investigated (Stroncek et al 1999; Hong
et al 2003). Although gene therapy remains a viable potential
option, safety issues and problems with robust expression in
vivo remain barriers to its clinical application.
Conclusions
MPS II is a heterogeneous, progressive X-linked lysosomal
storage disease, the management of which requires lifelong
attention to the multisystem involvement, Recent clinical
trials have demonstrated that enzyme replacement therapy
with intravenous idursulfase is a safe and effective treatment
modality for the somatic, but likely not the CNS manifesta-
tions of MPS II. As with other lysosomal storage disorders,
enzyme replacement therapy represents a treatment rather
than a cure for this disease; long term studies evaluating the
effi cacy of this therapy are indicated.
Approaches which are likely to ameliorate the progres-
sive CNS manifestations in children with severe MPS II are
still in preclinical stages, and will be a needed addition to the
therapeutic armamentarium for this condition.
It is anticipated that rare disease registries such as the
HOS will provide a mechanism through which experience
beyond clinical trials can be documented and made available
to centers which care for these patients.
Disclosures
Neither author has any confl icts of interest to disclose.
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