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In: Neurochemistry of Metabolic Diseases ISBN 978-1-61209-671-1
Editors: Sankar Surendran, pp. © 2011 Nova Science Publishers, Inc.
Chapter 8
Enzyme Replacement Therapy for
Lysosomal Storage Diseases
Shunji Tomatsu1,
, Adriana M. Montaño1, Angela Catalina Sosa
Molano1,2
, Daniel Rowan1, Jonathan P. Hintze
1, Clarissa Gutiérrez
Carvalho3, Andressa Federhen
3,
Taiane Alves Vieira3, Roberto Giugliani
3, Grzegorz Węgrzyn
4,
Akemi Tanaka5, Yasuyuki Suzuki
6 and Tadao Orii
7
1Departments of Pediatrics and Biochemistry and Molecular Biology,
Saint Louis University, St. Louis, Missouri
2Institute for the Study of Inborn Errors of Metabolism,
Pontificia Universidad Javeriana, Bogota, Colombia 3Medical Genetics Service/HCPA, Department of Genetics/UFRGS and
Postgraduate Programs in Medical Sciences and in Adolescent and Child Health,
UFRGS, Porto Alegre, Brazil 4Department of Molecular Biology, University of Gdansk,
Kladki 24, 80-822 Gdansk, Poland 5Department of Pediatrics, Osaka City University Graduate School of Medicine,
Osaka, Japan 6Medical Education Development Center (MEDC),
Gifu University School of Medicine, Gifu, Japan 7Department of Pediatrics, Gifu University, School of Medicine, Gifu, Japan
Abstract
Therapies for lysosomal storage disorders (LSDs) have been developed clinically
and experimentally (Table 1). These include hematopoietic stem cell therapy (HSCT),
Tel: 314-977-9292; Fax: 314-977-9105; e-mail: [email protected]
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 2
enzyme replacement therapy (ERT), and gene therapy, all of which lead to the partial
restortion of enzyme activity. Substrate reduction therapy (SRT) and the use of
pharmacological chaperones have also been attempted. Although HSCT is not entirely
effective, impairment of cognitive function has been prevented if the patients are treated
at an early stage. However, HSCT still brings concerns because of the high morbidity and
mortality rates. Gene therapy is still experimental at this moment. SRT is orally
administered and clinical assessment is under investigation.
Treating LSDs with ERT relies on the cellular uptake of exogenous enzyme by
receptor-mediated endocytosis. ERT using macrophage-targeted
recombinant β-
glucocerebrosidase is successful in treating the nonneuronopathic form of Gaucher
disease, which opened the door to the development of this treatment for further LSDs.
ERT was also approved for use in patients with Fabry and Pompe diseases,
mucopolysaccharidosis I (MPS I), MPS II, and MPS VI. Patients treated with ERT had
clinical improvement of somatic manifestations and improved quality of life. However,
there are several limitations with current regular ERT: 1) immunological issues (raising
the antibody level leads to reduced efficacy), 2) rapid clearance from blood circulation, 3)
limited effect on neurological and skeletal symptoms, 4) high cost, and 5) lifelong
dependence on weekly infusions.
Thus, in spite of substantial success of ERT, no curative therapies exist for LSDs,
especially with bone dysplasia and central nervous system (CNS) involvement.
Supportive measures are also used to treat the clinical manifestations of LSDs.
Medications are used for palliative care, such as non-steroidal anti-inflammatory drugs
for joint pain, antibiotics for pulmonary infections and oxygen supplementation for
pulmonary compromise. Surgical interventions such as cervical fusion, spinal cord
decompression, osteotomy, and hip replacement are often required.
In this chapter we describe the efficacy of ERT and its limitations in comparison
with other therapeutic options available for a particular group of LSDs, The
Mucopolysaccharidoses (MPS).
I. Introduction
Enzyme replacement therapy (ERT) is an established strategy of treating lysosomal
storage diseases (LSDs) including mucopolysaccharidoses (MPS). Tremendous progress in
research toward development of ERT has been made in the last three decades. ERT using
genetically engineered human enzyme manufactured by recombinant DNA technology in
high-output cell lines is an established treatment for several LSDs based on the unique ability
of human cells to bind and transport exogenous enzyme into the lysosomal compartment. In
Gaucher disease, delivery of enzyme to affected cells was achieved by modifying the N-
linked carbohydrate on the enzyme to expose core mannose residues [1,2], enabling
the
enzyme to bind to the mannose receptor (MR), which is highly abundant on cells of the
reticuloendothelial system [3,4]. These findings led to achievement of clinical management of
Gaucher disease by ERT with dramatic clinical results [5-7]. The MPS are a group of LSDs
caused by deficiency of the lysosomal enzymes needed to degrade glycosaminoglycans
(GAGs), which are long unbranched polysaccharides consisting of repeating disaccharide
units [8]. GAGs include: chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate
(HS), keratan sulfate (KS), and hyaluronan. Their catabolism may be blocked singly or in
combination depending on the specific enzyme deficiency. Lysosomal accumulation of GAG
molecules results in cell, tissue, and organ dysfunction. In MPS, the undegraded or partially
Enzyme Replacement Therapy for Lysosomal Storage Diseases 3
degraded GAGs are stored in lysosomes and/or secreted into the blood stream and
subsequently excreted in urine. There are 11 known enzyme deficiencies that give rise to
seven distinct MPS.
Table 1. Therapies available to reduce storage materials
HSCT: hematopoietic stem cell therapy, SRT: substrate reduction therapy, SOT: substrate optimization
therapy, RNAi: RNA interference, NA: not available.
Figure 1. A. Clinical picture of three year-old female patient with the severe form of MPS I (Hurler
syndrome) (kindly provided by Dr. Roberto Giugliani). At that time she was 3 year-old (weight 15kg, height
83cm). She had a marked lumbar kyphosis, coarse hair, abnormal facies, delay on speech, corneal clouding,
mild articular restriction, hepatosplenomegaly, and upper airway infections. Somatic involvement was
improved after starting of ERT. The genotype was p.W402X/p.W402X defining a severe form and the most
popular mutation among Caucasian MPS I patients. B. Clinical pictures of MPS II patients (spectrum of
disease severity) (kindly provided by Dr. T. Orii). Patients with Hunter syndrome were called MPS II
following Hurler syndrome (MPS I) since Hunter and Hurler syndromes were caused by the deficiency of a
different enzyme. The historical classification, an arbitrary categoriaation of symptom clusters, was
subsequently proven to be inadequate. Biochemically, patients with the attenuated disease forms cannot be
reliably separated from the most severely affected patient either, in all enzyme activity is low, certainly below
10 % of normal, and usually below 1 %. Therefore it is better to speak of MPS II as a spectrum of disease
ranging from most severe to patients with an attenuated phenotype. The important clinical characteristics of
MPS II are: 1) It affects most tissues and organs, 2) There is a spectrum of disease, both as regards severity as
well as symptom heterogeneity, 3) It is a progressive disease, and eventually leads to the patient being left
debilitated, 4) The morbidity is severe, with patients losing dexterity, mobility, vision, hearing, having severe
Treatment Animal models Clinical trial (investigational) Approved (standard care)
Degradation
ERT (intravenous) I, II, IIIA, IIIB, IVA, VI, VII I, II, IVA, VI I, II, VI
ERT (Intrathecal) I, II, IIIA, IIIB, VI, VII I, II, VI
IIIA (planned in 2010)
Gene therapy I, II, IIIA, IIIB, IVA, VI, VII I, II (unsuccessful)
IIIA (planned in 2010)
HSCT I, VI, VII I, II, IIIA, IIIB, IVA, VI, VII I (under 2 years)
Chemical Chaperon NA NA
SYNTHESIS
SRT I, II, IIIA, IIIB, IVA, VII I, II, IIIA, IIIB
SOT IIIA
RNAi IIIA, IIIB
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 4
cardiac and respiratory conditions, and so on. In most patients life span is reduced, at least if the disease is
left untreated (long term data on HSCT or ERT is under investigation).
Clinical Features of MPS: The MPS share many clinical features, although in variable
degrees. Most MPS patients are asymptomatic at birth, with subsequent onset of clinical signs
and symptoms. These include a chronic and progressive course, multisystem involvement,
organomegaly, dysostosis multiplex, and abnormal facies. Hearing, vision, airway,
cardiovascular function, and musculoskeletal and connective tissue are also affected.
Profound neurological impairment is a characteristic of MPS I (Hurler syndrome) (Figure
1A), the severe form of MPS II (Hunter syndrome) (Figure 1B, Figure 2), all subtypes of the
MPS III (Sanfilippo syndrome) (Figure 3), and MPS VII (Sly syndrome) (Figure 4A), while
MPS IV (Morquio syndrome) (Figures 4B,5,6) and MPS VI (Maroteaux-Lamy syndrome)
(Figure 7) have characteristic bone lesions without CNS involvement. There is clinical
similarity between different enzyme deficiencies and, conversely, a wide spectrum of clinical
severity within any one enzyme [8]. In nearly all cases, except for the milder ones, the disease
is fatal with an average life expectancy of one to two decades without treatment.
Figure 2. Skeletal/joint problem in an MPS II patient with the attenuated form (20 years old; 120 cm tall)
(copyright belongs to Gifu and Saint Louis Universities). A. Hip and Knee restriction and contractures. B.
Metatarsal abnormalities and contractures of toes. C. Shoulder and elbow restriction and contracture. D. Claw
hands. Although this patient had visceral and skeletal/joint involvement, no mental retardation has been
recognized. Hepatosplenomegaly and the range of motion for the joints were improved after ERT at the age
of 20 years.
Enzyme Replacement Therapy for Lysosomal Storage Diseases 5
Incidence: The MPS can be found worldwide. Although the incidence of MPS is
estimated as 1:25,000 live births, the incidence of a particular type of MPS varies [9]. There
are no studies about the incidence of MPS in the USA, but we estimate that approximately
200 newborns affected with MPS are born annually.
Figure 3. A. Progression of the disease in an MPS III male patient with the severe form (kindly provided by
Japanese Society of the Parents and the Families with MPS). There are four types of MPS III based on
enzyme deficiency (MPS IIIA, B, C and D). Patients make up biochemically diverse, but clinically similar.
MPS III is a progressive disorder with multiple organ and tissue involvement. Patients have variable onset
but usually obvious between 2 and 8 years of age. Progressive and severe central nervous system
degeneration is characteristic with mild somatic and skeletal disease. The patients survive into the 2nd
decade. Airway obstruction and cardiac failure are the most common direct causes of death. This patient had
no sign and symptom at 6 months old with normal appearance. However, at three to five years old, he had
started with delayed development, restlessness, and hyperactivity. By eight year old, he revealed very
difficult behavior (aggressively, temper trantrums, destructive behavior, and physical aggression) and
insomnia. Language and understanding was gradually lost: speech development delayed and poor
articulation. By 14 years old, he developed severe neurologic degeneration and rapid deterioration of social
and adaptive skills. He slowed down and lost the ability to walk. B. MRI in a five year-old MPS IIIA patient.
Brain cortex is markedly atrophic. High density signal is observed in cortex by T2-weighted axial image.
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 6
Figure 4. A. Clinical pictures of three patients with an attenuated form of MPS VII (kindly provided by Dr. T.
Orii). Case 1: An 8-year-old girl homozygous for the p.A619V mutation, had a successful allogeneic BMT at
12 years old, donored by an HLA-identical unrelated female to replace the deficient enzyme (see the text).
She revealed the clinical features of hepatosplenomegaly, umbilical herniation, slight bone deformities,
moderate mental retardation and short stature. Case 2: 24 year-old boy homozygous for the p.A619V
mutation, showed similar clinical features as Case 1 expressed. Case 3: A 7 year-old girl homozygous for
p.R382C mutation, revealed unique clinical features of umbilical herniation, Morquio-like severe bone
deformities, short stature, normal intelligence, hepatosplenomegaly, normal facies and no abnormal granules.
B. Clinical pictures of MPS IVA patients (Copyright permission from Gifu University). Case 1: This 31 year
old female patient with a severe form of MPS VII shows skeletal deformities typical of Morquio A syndrome.
She is 90 cm tall, showing pectus carinatum, bilateral genu valgum, diffuse corneal clouding, atlantoaxial
subluxation, and hyperlaxity of joints. The genotype is c.1288_1289delCA/c.1288_1289delCA. Case 2: This
18 year old male patient with an intermediate form is 135 cm tall with the milder skeletal deformities of
pectus carinatum, bilateral genu valgum, and hyperlaxity of joints and corneal clouding. The genotype is
p.R94G/p.N204K. Case 3: This 25 year old male patient with a mild form is 157 cm tall and has milder
skeletal deformities of thoracolumbar gibbbus, mild platyspondyly and anterior wedging of the bodies in X-
rays but no genu valgum. The genotype is pN204K/pN204K. All three patients have normal intelligence.
Enzyme Replacement Therapy for Lysosomal Storage Diseases 7
Figure 5. Top panel: Skeletal/joint problem in an MPS IVA patient (10 years old; 123 cm tall) (Copyright
permission from International Morquio Organization). The genotype is p.M41L/ p.M41L defining the
attenuated phenotype. He had characteristic features of MPS IVA and underwent several surgical operations
such as osteotomy, hip surgery and cervical fusion. A. Knock-knee; B. Metatarsal abnormalities and flat foot
with sandal gap; C. Floppy wrist; D. Protrusion of the chest and deformity of the ribs; E. Laxity of joint.
Bottom panel: Skeletal problems in an MPS IVA patient (3 years old; 85 cm tall) (Copyright permission from
International Morquio Organization). This three year-old male patient showed a severe bone deformity:
protrusion of the chest, kyphosis, and genu valgum are characteristic with waddling gait.
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 8
Figure 6. A. Lateral view of progressive changes of the spine with age in the patient (Copyright permission
from International Morquio Organization). 1 day: a sacral dimple was noted at delivery and suspected
anterior beaking at the level of L2 was seen. 2 months: the anterior beaking was more prominent at the level
of L2 with kyphosis. 15 months: Flaring of the anterior lateral ribs was observed. Kyphosis centered at L2
and flamed-shaped anterior beaking of the vertebral bodies were marked. 32 months: Accentuated dorsal
thoracolumbar kypholordosis with gibbous deformity was remarkable. Advanced platyspondyly, irregularity,
and anterior beaking of the vertebral bodies characteristic of Morquio syndrome were prominent. Mutation
analysis of the GALNS gene by PCR of all exons and subsequent direct sequencing indicated that the patient
had a novel missense mutation with c.278T>A in exon 3. The mutation present in the other allele was not
identified. At the current age of 5 years and 8 months, the patient has nearly stopped growing at height of
97.7 cm and at weight of 15.7 kg. The patient has a majority of the common skeletal findings of MPS IVA
including prominent chest and forehead, hypermobile joints, wrist weakness, diffuse platyspondyly,
hypoplasia of the superior aspect of the odontoid process of C2, narrowing of craniocervical junction, mild
scoliosis, thoracolumbar kyphosis and mild organomegaly. B. MRI of a 4 year-old Morquio A patient
(Copyright permission from International Morquio Organization). A baseline study of the upper cervical
anatomy is recommended no later than 2 years or at diagnosis using flexion/extension X-ray films. If severe
pain or pain associated with weakness of strength or tremors (or clonus) in the arms or legs occur, the patient
should have studies of the neck to evaluate for the slippage (subluxation) of the neck vertebrae and
compression of the spinal cord. MRI will be taken with the head bent forward (flexion) and with the neck
back (extension) and will be monitored annually to check the situation of cervical spine in a patient aged.
This MRI shows substantial spinal cord compression in C1-C2 and L1-L2 portion.
1 day 2 mo 15 mo 32 mo
A.
B.
• Spinal cord compression
• Hypoplasia of odontoid process
4 year-old patient Normal
Enzyme Replacement Therapy for Lysosomal Storage Diseases 9
Figure 7. Progression of the disease in a female patient with the severe form of MPS VI (kindly provided by
Dr. R. Giugliani). This patient was diagnosed at 1year-old with mild visceral and skeletal disease. She is 10
year-old with the progression of the disease. She sleeps with continuous positive airway
pressure (CPAP) and has mitral valve thickening, MRI with hydrocephalus (mild - conservative
management), corneal clouding and neuro-sensorial deafness. Her intelligence is normal. The patient attends
normal school but has difficult in walking because of the skeletal disease. Her height and weight are 97 cm
and 18 kg.
Therapeutic options: Therapies for MPS have been developed experimentally and
clinically. These include hematopoietic stem cell therapy (HSCT), ERT, gene therapy, and
substrate reduction therapy (SRT), all of which lead to the partial restortion of the enzyme
activity or inhibition of synthesis of GAGs. HSCT is not entirely effective and has a relatively
high mortality rate mainly due to the development of graft versus host disease [10-11].
Treating MPS with ERT relies on the cellular uptake of the enzyme by receptor-mediated
endocytosis.
ERT tested in animal models has been quite successful leading to application in human
patients [12-16]. ERT was FDA approved for use in patients with MPS I [8,17], MPS II
[18,19] and MPS VI [20-23]. Patients treated with ERT had clinical improvement of somatic
manifestations and improved quality of life. Additional trials for MPS IVA and other type of
MPS are under way. ERT holds much promise for the treatment of MPS. However, there are
several limitations for ERT. 1) Current experiences with MPS animal models and human
clinical trials indicate that it is unlikely that therapeutic amounts of enzyme: i) cross the blood
brain barrier to provide correction of the CNS pathology and ii) reach the bone cells to correct
the skeletal pathology. Thus, only a small fraction of enzyme is delivered to bone and brain,
resulting in an unmet challenge to restore such lesions. 2) Over 50% of the patients treated
with regular ERT produce antibodies against the enzyme and have immune reactions [24-26].
3) In vivo, proteins are unstable and rapidly eliminated from circulation because of clearance
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 10
via glomerular filtration, endocytosis, phagocytosis, enzyme degradation, inhibitors, and
immune system processing [27-28]. Thus, ERT is not a complete curative strategy for MPS
disorders. As an alternative option, experimental gene therapies, HSCT and SRT for MPS are
under way in vivo [29-31] (Figure 8). Other supportive therapies such as surgical operations,
rehabilitation, and anti-inflammatory drugs are considered in combination.
Figure 8. Potential therapeutic approaches for MPS.
Overall, medical care is directed at treating systemic conditions and improving the
person's quality of life. Supportive or symptomatic management can improve the quality of
life for affected individuals and their families. Follow-up of affected individuals to
anticipate possible complications and to provide early intervention maximizes outcome. We
review the optional therapies for MPS especially ERT and summarize advantages and
disadvantages of this therapy in comparison with other options (Table 2).
Table 2. Comparison among therapies
Enzyme Replacement Therapy for Lysosomal Storage Diseases 11
*Although HSCT is generally supposed to have a high incidence of mortality rate, most cases were
performed in a progressive stage and above 2 years. Therefore, there is no statistically significant
clinical outcome when the patients are treated at the presymptomatic stage. NA: not available.
II. Enzyme Replacement Therapy for MPS
ERTs are currently in use or are being tested for use in MPS. ERT has proven useful in
reducing non-neurological symptoms and pain. ERT for MPS type I, II and VI are available
and ERT for MPS IVA is under clinical trial. Current ERT does not cross the blood-brain
barrier (BBB), therefore no effect on CNS disease is anticipated. With the success of ERT for
MPS demonstrated by clinical trials, an increased effort is underway to improve
responsiveness to ERT and to develop other forms of therapy directed at areas/organs that
may not be responsive to ERT.
Clinical Trials
Mucopolysaccharidosis I (MPS I):
1. Phase I/II clinical trial: The Phase I/II open label study included ten individuals with
attenuated MPS I aged from five to 22 years, treated with doses of 0.58 mg/kg of
human α-L-iduronidase once a week for 52 weeks. This study showed improvement
in liver size, growth, joint mobility, breathing, sleep apnea and urinary GAG
excretion. Increased ability to perform daily functions was reported [17]. A six-year
follow-up of five of the treated individuals showed sustained improvements in joint
range of motion and sleep apnea and no progression of heart disease, but evidence of
progression of valvular involvement [32].
2. Phase II/III clinical trial: The Phase III double-blind placebo-controlled study
included 45 individuals with MPS I (most classified as Hurler-Scheie) treated for 52
weeks with a 26-week placebo phase [33]. This study showed statistically significant
improvements in pulmonary function and a six-minute walk test (6MWT) and clear
biologic effect with reduction in urinary GAG excretion and liver volume. Patients
who had significant sleep apnea and difficulties in shoulder flexion at the beginning
of the study improved significantly. Laronidase was well tolerated and nearly all
patients developed IgG antibodies without apparent clinical affect. In 2009, Clarke et
al, published the results of a prospective, open-label study, with 40 patients, aged
from six to 43 years, who received 0.58 mg/kg of laronidase weekly for 182 weeks.
ERT HSCT Gene therapy SRT
Type Enzyme Cell Gene Inhibitor
Pathway Degradation Degradation Degradation Synthesis
Administration Intravenous, intrathecal Intravenous Intravenous Oral
Cost Very high Medium High Low
Frequency Weekly life time One time permanent every 1-5 years? Daily life time
Mortality Low High* Moderate? Extremely low (if any)
Adverse effect Infusion reaction GVHD Cancer Minor (if any)
Immune response Chemotherapy Immune response
CNS Not effective Effective if early NA Effective if early, supportive if late
IT ERT under way
Bone Refractory, effective if early Refractory, effective if early Refractory, effective if early Not tested
Others General anesthesia Combined with other therapy
Donor selection
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 12
This study confirmed a favorable safety profile and the improvements which had
been seen in phase III study [34]. Other case reports representing smaller numbers of
treated patients show variable responsiveness to treatment. The heterogeneity of
treated patients published to date complicates any conclusions that can be drawn. It
appears that the ability of ERT to reverse disease symptoms in individuals with
attenuated disease relates closely to the burden of disease prior to commencement of
treatment.
3. Phase IV studies: An open label prospective study evaluated 20 children with MPS I
under five years of age (16 with Hurler syndrome and four with Hurler-Scheie
syndrome) receiving laronidase 0.58 mg/kg or 1.16 mg/kg, weekly for 52 weeks. Out
of the 20 patients, four received twice the dose in the second half of the study, as
they showed GAG excretion greater than 200 mg/g creatinine at week 22. The main
findings included good laronidase tolerance in patients under five years of age at
both doses, reduction of GAG levels by approximately 50% in the 13th week of
treatment and 61.3% at week 52. The liver edge decreased 69.5% at palpation. There
was a decrease in the number of patients with left ventricular hypertrophy and
apnea/hypopnea [35].
4. Other trial: An open label, multinational, randomized, 26 weeks long dose
optimization study was reported in 2009 [36]. In this study four different regimens of
laronidase (0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every
week or 1.8 mg/kg every two weeks) were administered to 33 patients with MPS I.
The four treatment regimens showed no significant differences in the reduction of
urinary GAG excretion and liver size, and regimens were considered safe. Out of the
four groups of patients, those who used the approved dose (0.58 mg/kg once a week)
showed the least adverse effects. Although the long-term effects of the use of
alternative regimes are unknown, the regimen of 1.2 mg/kg every two weeks may be,
according to the authors, a convenient and acceptable alternative to patients,
particularly those who have difficulties in performing weekly infusions.
Mucopolysaccharidosis II (MPS II):
1. Phase I/II clinical trial: A phase I/II study enrolled 12 patients into a randomized,
double-blind, placebo controlled trial for 24 weeks followed by an open label
extension study. The dose of idursulfase was 0.15, 0.5 and 1.5 mg/kg every other
week for each group. Urinary GAG level were markedly decreased within 2 weeks
following the initial dose. This reduction was maintained through 48 weeks. Both
spleen and liver volumes were decreased at 24 and 48 weeks. The average walking
distance in the 6MWT significantly improved after 12 months of idursulfase. The
results of this trial indicated that idursulfase is generally well tolerated and it has
effects on several aspects of MPS II that may confer clinical benefit with long-term
therapy [37].
2. Phase III clinical trial: Clinical efficacy of ERT was shown in a randomized, double-
blinded, placebo-controlled, multicenter and multinational study of 96 patients [19]
in phase III clinical trial. Patients were randomized into three treatments arms: 0.5
mg/kg of idursulfase weekly, 0.5 mg/kg idursulfase every other week (EOW) and
placebo. After one year of treatment, patients in the weekly idursulfase group
Enzyme Replacement Therapy for Lysosomal Storage Diseases 13
compared to the placebo group demonstrated statistically significant improvement of
the primary endpoint, a composite score consisting of distance walked in 6MWT and
the percent of predicted forced vital capacity based on the sum of ranks of change
from baseline. A smaller difference was found for idursulfase EOW compared to
placebo group. Liver and spleen volumes decreased by over 20% after 18 weeks of
treatment in both idursulfase groups. After 53 weeks, about 80% of patients with
hepatomegaly who were receiving idursulfase weekly or EOW had normal liver
volume and spleen volume remained significantly reduced in these groups. The
urinary GAG levels in the idursulfase groups were significantly different than that of
the placebo group after one year of treatment and the response in the weekly group
was significantly greater than that seen in the EOW group. An improvement in elbow
mobility between the weekly idursulfase group compared to placebo was observed.
Based on the larger clinical response in the weekly compared to the every other week
group, idursulfase was approved for the treatment of MPS II in both the US and
European Union at a dose of 0.5 mg/kg weekly.
3. Others: Patients with the severe form of MPS II treated with idursulfase would be
expected to have somatic stabilization, but the overall benefit will have to be
evaluated depending of the somatic disease burden and rate of progression of the
CNS disease. According to Wraith et al (2006) [38], the patients with severe CNS
involvement may be offered the possibility of treatment for a ‘trial’ period of 12-18
months, after which time a decision should be made as to whether to continue.
Experience in treating children under age of 5 years with idursulfase is limited.
Mucopolysaccharidosis IVA (MPS IVA):
ERT by using recombinant human native GALNS is now under Phase I/II clinical trial
for treatment of patients with MPS IVA. GALNS is produced in a continuous CHO cell line
and is a purified form of the natural lysosomal enzyme GALNS. It will be anticipated that
efficacy of therapy will be limited in a short term observation compared to other types of
MPS since MPS IVA is a systemic bone disease and that careful long term observation is
required to evaluate treatment.
Mucopolysaccharidosis VI (MPS VI):
Extensive preclinical studies were completed in a feline model of MPS VI [39] that
established the dose, safety, as well as efficacy in reversing storage, and limiting bone disease
when started very early in life. These preclinical studies were followed by Phase I/II, Phase II
and Phase III human clinical trials [40]. Significant improvements in 12-minute-walk test,
nearly significant improvement in 3-minute stair climb and significant reduction in urinary
GAG levels were demonstrated in the 24-week, randomized, double-blind Phase III trial [41].
On the long-term follow-up, improvement in endurance on the walk test and stair climb,
reduction in urinary GAG positive effects on puberty and growth, and pulmonary function
were maintained in clinical study subjects from all trials, with observation times up to a
maximum of five years with regular ERT [40,41].
A case study has shown improvement following ERT of pulmonary function leading to a
reversal of tracheostomy intubation in an MPS VI patient [42]. Another case study has shown
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 14
reversal of papilledema and improved vision in an 11-year old MPS VI patient, followed on
ERT maintained during follow-up of 130 weeks [43]. A case series of six MPS VI patients
showed stabilization of visual acuity after treatment with ERT for 144 weeks [43].
Early introduction of recombinant human arylsulfatase B (rhASB) produced a state of
immune tolerance and improved enzyme effectiveness in the cat model; hopefully, similar
findings will be demonstrated in humans after early introduction of ERT [44]. An open label,
single center case control study compared a pair of siblings, one of whom was diagnosed in
utero [45]. Both were treated with rhASB, and the primary end-point was clinical status of the
younger sibling at age 3.6 years after 182 weeks of therapy compared with sibling 1, who had
no ERT at 3.6 years. No adverse effect occurred and the major differences were that sibling 2
had no scoliosis, minimal joint involvement, normal facial appearance, and normal cardiac
valves. Both had decreased growth rate between birth and 3.6 years. This sibling control
study provides the first evidence in patients with MPS VI that early initiation of ERT may
provide an improved clinical outcome compared with reported studies of affected older
children, adolescents and adults.
Unmet Challenges for ERT
1. Delivery of the enzyme to bone: Most of the enzyme-based drugs are delivered to
major visceral organs like liver and spleen and only a small amount of enzyme is delivered to
bone and brain. Many lysosomal enzymes have a short half-life because of rapid clearance in
liver by carbohydrate-recognizing receptors, particularly the
mannose receptor (MR) that is
highly abundant on Kupffer cells [3] or the mannose-6-phosphate receptor (M6PR). Although
a fraction of enzyme reaches bone marrow, a slight amount reaches bone, especially the
cartilage cells in the avascular growth plate. Therefore, it is still a challenge to achieve
clinical efficacy for the skeleton, especially for diseases with multi-bone involvement like
MPS IVA. Thus, improvement of bone lesions in Gaucher patients by ERT is quite limited
even after a long term treatment [44]. Similarly, very little improvement in bone was seen in
clinical trials on MPS I. The current conventional ERT targeting both MR and M6PR may not
work efficiently on bone and cartilage lesions. To solve the intrinsic issue, an alternative
approach of ERT is devised in combination with bone targeting system. Hydroxyapatite (HA)
is a positively-charged, major inorganic component in a hard tissue (bone) and does not exist
in soft tissues. A drug attached to HA may be released in bone resorption process and
targeting a drug on HA could be a potential strategy for a selective drug delivery to bone and
cartilage cells. Estradiol uptake by bone was enhanced and osteoporosis was prevented by
using six stretch of Glu (E6) targeted hormone [46-47]. This bone-targeting system was
applied to a large molecule, an enzyme (tissue nonspecific alkaline phosphatase), showing
that the tagged enzymes were delivered more efficiently to bone and that the clinical and
pathological improvement in systemic bone disease, hypophosphatasia, was observed [48-49].
Human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) which is deficient in MPS IVA
patients was also bioengineered with the N-terminus extended by the hexa-glutamate
sequence (E6) to improve targeting to bone (E6-GALNS). The E6-GALNS tagged enzyme
Enzyme Replacement Therapy for Lysosomal Storage Diseases 15
had markedly prolonged clearance from circulation, giving over 20 times exposure time in
blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with
residual enzyme activity. The pathological findings in adult mice treated with tagged enzyme
showed substantial clearance of the storage materials in bone, bone marrow and heart valves,
especially after 24 weekly infusions. These findings indicate the feasibility of using tagged
enzyme to enhance delivery and pathological effectiveness in MPS IVA mice [50].
2. Delivery of enzyme to the CNS: IV infusion of recombinant proteins does not lead to
transfer of proteins across the BBB. Various means to provide enzyme to the CNS are
currently being researched. These approaches include cerebrospinal fluid (CSF) instillation of
enzyme via direct injection, continuous pumps, microcapsule implants, and production of
chimeric recombinant proteins, enabling passage across the BBB. A clinical trial of
intrathecal (IT) ERT for MPS I, II and VI is now underway in patients who have evidence of
spinal cord involvement.
The IT ERT could hold promise as a treatment for the CNS manifestations of LSDs.
Treatment via the CSF represents a potential method of delivering recombinant enzyme
across the BBB. Experiments in animal models of MPS I, MPS II, MPS IIIA and MPS IIIB
have shown that ERT delivered via the IT route distributes throughout the CNS and
penetrates brain tissue, where it promotes clearance of lysosomal storage material. Studies are
underway to investigate the safety and efficacy of IT ERT in patients with MPS I, II and VI
[51-55]. The clinical trial of IT ERT for MPS IIIA is expected to start in 2010.
MPS VI patients often develop spinal cord compression during the course of the disease
due to GAG storage within the cervical meninges, requiring neurosurgical intervention, as
intravenous ERT is not expected to cross the BBB. In recent reports, the use of IT ERT was
performed for a MPS VI child with spinal cord compression whose parents initially refused
the surgical treatment. Assessments were performed at baseline, with clinical, neurological
and biochemical evaluations, urodynamic studies and MRI of the CNS. Despite significant
urodynamic improvement and some neurological amelioration, the patient developed
worsening of walking capacity. After IT ERT was started, the patient presented with a
generalized hypotonia and a life-saving surgical fixation of the neck was then performed. The
results observed on this MPS VI patient suggest that instability of the cervical vertebrae could
be unmasked by IV ERT as joint storage is reduced, and the decrease in neck stiffness and
stability could confound the expected improvement of spinal cord compression manifestations
following IT ERT. Thus, IT ERT for MPS should be evaluated carefully with assessment of
its adverse effect [56].
Another approach for CNS involvement is to utilize alternative uptake mechanisms
that
rely on protein-based, rather than oligosaccharide-based, targeting determinants. Some studies
have focused on the use of small basic peptides, like human immunodeficiency virus
TAT, to
enhance the delivery to specific tissues [57-58]. Others have demonstrated the feasibility of
this approach using insulin-like growth factor-2, a peptide ligand for the M6PR or the low-
density lipoprotein receptor [59-61].
The critical issue for ERT is that proteins have complex secondary and tertiary structures
that make them susceptible to conformational changing factors which lead to instability [62].
In vivo, many proteins are unstable and/or rapidly eliminated from circulation because of
clearance via glomerular filtration, endocytosis, phagocytosis, enzymatic degradation,
inhibitors, and antibodies [27-28]. The previous clearance studies on phosphorylated
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 16
lysosomal enzymes showed a rapid clearance (half-life time): α-iduronidase, 0.9 min [62]; α-
galactosidase A, 2 - 5 min [63]; glycosylasparaginase, 4 min [64]; β-glucuronidase, 5.2 min
[65-66]; and GALNS, 3 min [67]. Recent studies have shown that longer treatment with
higher doses of enzyme or enzyme modified to effect slower circulation resulted in improved
therapeutic responses in brain in mouse model [66,58-71]. These results indicate that
therapeutic enzyme can be delivered across the BBB if administered in higher doses than used
in conventional ERT trials or if the enzyme is modified to attain a longer circulation during a
certain period.
3. Side effects:
A. Infusion reactions: Infusion-related reactions that may occur with use of ERT are
seen in treatment of LSDs. The etiology of the more severe forms of these non-allergic
reactions, referred to as anaphylactoid, is unknown. Current evidence suggests that
anaphylactoid (as opposed to anaphylactic) reactions are not immune mediated [72].
Anaphylactoid reactions refer to an identical clinical pattern with anaphylaxsis, however it is
non-IgE mediated. Certain allergens including drugs can trigger the mast cell cascade directly
without involving IgE as the initial mediator. Anaphylactoid reactions therefore do not
require prior sensitization as they are direct mass cell releasers and may produce
anaphylaxis-like reactions in a dose-dependent manner. By contrast, classic anaphylaxis is
not dose-dependent as the immune system is primed to recognize even minute amounts of the
allergen and able to amplify the reaction via IgE mediation. For practical purposes, we can
consider the clinical effects and management of anaphylaxis and anaphylactoid reactions to
be identical.
Most infusion-related reactions are mild, manifest as brief, insignificant decreases or
increases in heart rate, blood pressure, or respiratory rate. Other mild reactions are itching,
rash, flushing, and headache. Mild reactions can usually be managed by slowing the infusion
rate for several treatments and then slowly returning to the prior rate.
Pretreatment with anti-inflammatory drugs or anti-histamines is often done for ERT. If
mild or moderate infusion reactions (e.g., dyspnea, urticaria, or systolic blood pressure
changes) cannot be ameliorated by slowing the infusion rate, the addition of treatment one
hour before infusion with diphenhydramine and acetaminophen (or ibuprofen) to the regimen
usually resolves the problem. Pretreatment can typically be discontinued after six to ten
weeks.
Severe non-allergic anaphylactoid reactions such as major changes in blood pressure,
wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by
stopping the infusion and giving appropriate doses of subcutaneous epinephrine, IV
diphenhydramine, and hydrocortisone or methylpredinsolone. Subsequent infusions should
then be given at a significantly reduced rate with prednisone pretreatment 24 hours and eight
hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour
before the infusion, and IV methylpredinsolone just before beginning the infusion. It is
unknown at this time whether the incidence or severity of infusion-related reactions is
different for patients younger than age five years with severe respiratory compromise or with
severe CNS disease.
B. Immune response: One intrinsic limitation of current ERT is the induction of anti-
enzyme antibodies, leading to the neutralization of the infused protein by the immune system.
ERT commonly produces a cellular or humoral immune response to the therapeutic enzyme,
with reported rates of antibody formation in treated patients ranging from 13% for Gaucher
Enzyme Replacement Therapy for Lysosomal Storage Diseases 17
disease to 90% and 100% for MPS I, MPS VI and Pompe disease, respectively [26,73,74].
IgG anti-idursulfase antibodies were detected in 46.9% of MPS II patients in each idursulfase-
treated group. The reduction in urinary GAG levels in antibody-positive patients was about
two-thirds of that seen in antibody-negative patients. In contrast, there was no association
with the presence of antibodies and adverse events or with clinical assessments.
Immune response may depend on the nature of the replaced protein, the genetic
background of the patient, the dose of the infused enzyme, the frequency of treatment, the
structural differences between the infused and defective protein, the presence or absence of
residual mutant protein in the individual and other environmental factors that could increase
the susceptibility to develop an immune response. The source of the protein in terms of
processing, production, and post-manufacture storage and handling are additional factors that
affect the immunogenicity of the enzyme [74,75]. There is a correlation between genetic
mutations and immune response. Especially, patients with null type of mutation and
subsequent severe clinical phenotypes could show a more vigorous immune response [74].
There are potentially two main adverse effects of an immune response to ERT. The first
immune-mediated complication is the development of hypersensitivity (anaphylactic)
reactions during or immediately after administration of the enzyme. The second potential
complication involves the effect of circulating reactive antibodies to the replaced protein
resulting in the reduction of the efficacy of ERT [73,74,76].
Antibody levels have not been precisely predictive of hypersensitivity or other adverse
reactions to therapy, although the presence of antibodies is likely a factor in infusion-
associated adverse events [26]. Thus, IgG antibodies against infused enzymes are present in
most patients receiving ERT, although titers may wane with time in some patients [26,69].
Recent report shows that during ERT, urinary GAG excretion is higher in MPS I and MPS VI
patients with very high antibody titers to enzyme, resulting in reduction in the efficacy of
infused enzyme [26,77]. There is evidence in animal models that antibodies may partially
neutralize the effect of ERT by reducing the efficiency of uptake and redirecting the enzyme
to other target tissues [26,78]. The antibody probably binds to an epitope at or near the M6P
modification and sterically inhibits the protein from binding to the M6PR and being taken up
by the cell [79].
C. Current treatments to immune response: Protein therapeutics can be used as a drug
for the treatment of diverse diseases and in some cases represents the only available
therapeutic option. Therefore it is a particular challenge to avoid undesired side effects
derived from the unexpected immunogenicity of these drugs, which may decrease their
efficacy and safety [80]. In order to manage the immune response in patients, several
immunosuppressive protocols have been tested, including methotrexate, mycophenolate
mofetil and cyclosporin A with azathioprine [74,81]. A tolerization regimen was developed in
a canine model for MPS I that prevents a strong antibody response to the enzyme during ERT
by using cyclosporine A and azathioprine. In this study a decrease of immune response was
obtained due to a profound T cell suppression based on the maintenance of high plasma levels
of cyclosporine A and azathioprine [82]. A type 3 Gaucher patient, treated with ERT,
developed a progressively increasing titer of IgG antibodies that blocked the catalytic activity
of the enzyme. For a tolerant regimen, the patient was treated with a combination of plasma
exchange (to reduce the concentration of circulating antibodies), cyclophosphamide (as an
immune suppressor of B cells), intravenous Imuune globulins (to block Fc receptors and
control immune reactivity) and large doses of enzyme. A methotrexate regimen was used as
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 18
an immunosuppressive protocol to reduce recombinant human acid α-glucosidase-specific
antibody response in a mouse model [81]. The use of high amounts of protein in long-term
treatments or the induction and maintenance of immunosuppression protocols to the patients
in order to induce immune tolerance could be a disadvantage that raises adverse effect and
increases the cost of the therapy. The tolerance to the infused enzyme was obtained after one
to two years since the beginning of ERT. Those findings in preclinical and clinical trials
indicate that the induction of immune tolerance to the enzyme has a direct relevance to the
clinical management of the patient in terms of the efficacy and safety of treatments.
Therefore, an alternative novel tolerance protocol that minimizes the immune response
avoiding side-effects will be required.
III. Other therapeutic options
1. HSCT: HSCT using umbilical cord blood or bone marrow is a potential way of
providing sufficient enzyme activity to slow or stop the progression of the disease.
The beneficial effect of HSCT is thought to result from the replacement of deficient
macrophages by marrow-derived donor macrophages (Kupffer cells; pulmonary,
splenic, nodal, tonsilar, and peritoneal macrophages; and microglial cells) that
constitute an ongoing source of normal enzyme capable of gaining access to the
various sites of storage [84]. Although HSCT may modify disease progression and
improve survival in some children, it is not curative. HSCT should be used only in
carefully selected children with extensive pretransplantation clinical assessment and
counseling in whom systematic long-term monitoring of the results will be possible.
In general, the clinical outcome of children undergoing HSCT is varied and depends on
the degree of clinical involvement and the age of the child at the time of transplantation.
Adults have not undergone HSCT. Failure to achieve stable engraftment and graft-versus-host
disease represent significant barriers to successful HSCT for many children [85-87]; thus, the
procedure carries a high risk of morbidity and mortality.
HSCT has been successful in reducing the progression of some findings in children with
severe MPS I [88-90]. Although the heterogeneity of the disease makes interpretation of the
outcomes of HSCT somewhat difficult, available data show that successful HSCT increases
survival, reduces facial coarseness, as well as hepatosplenomegaly, improves hearing, and
maintains normal heart function. In a series of individuals predicted to have severe MPS I
based on the presence of known severe mutations, use of HSCT resulted in stabilization and
improvement of cardiac function with regression of hypertrophy and normalization of
chamber dimensions. In that cohort, HSCT did not appear to show significant effects on the
presence and progression of valvular involvement [91]. In contrast, the skeletal
manifestations and corneal clouding continued to progress at the same rate in children treated
with HSCT as in untreated individuals [92].
Neuropsychological responses to HSCT vary and are related to the age and intellectual
capacity of the child at the time of the engraftment. In children undergoing HSCT before
evidence of significant developmental delay (i.e., usually between ages 12 and 18 months),
HSCT appears to slow the course of cognitive decline. Children showing significant cognitive
impairment prior to undergoing HSCT do not appear to benefit developmentally. Recent
Enzyme Replacement Therapy for Lysosomal Storage Diseases 19
reports showed positive cognitive effects on MPS II and III patients after HSCT if the patients
are at an early stage [93].
In part because of increased longevity after HSCT, treated individuals develop increasing
pain and stiffness of the hips and knees, carpal tunnel syndrome, spinal cord compression,
and progressive thoracolumbar kyphosis. As a result, various orthopedic procedures intended
to maintain function and gait have been performed post-HSCT.
We had experienced a successful MPS VII BMT case (Figure 4A: case 1). Within 5
months after BMT at 12 years old, the enzyme activity of the recipient's lymphocytes
increased to normal range without acute or chronic GVHD. For the successive 31 months
post-BMT, the enzyme activity in her lymphocytes was maintained at almost normal levels
and excretion of urinary GAGs was greatly diminished. Ultrastructural findings demonstrated
no abnormal vacuoles and inclusion bodies in the cytoplasm of her rectal mucosal cells.
Especially notable were improvements in motor function. The patient was able to walk alone
for a long time without aid, and she even became able to ride a bicycle and take a bath. In
addition, recurrent infections of the upper respiratory tract and the middle ears decreased in
frequency and severity, and dyspnea on exertion, severe snoring and vertigo have
substantially improved. Thus, allogeneic BMT in this patient produced a better quality of life
and provided a more promising outlook [94].
2. Combined ERT and HSCT: The use of ERT in the peri-HSCT period should be
considered. In 26 patients [95] ERT used during this time period neither increased
nor decreased the frequency of engraftment or survival. Whether ERT begun prior to
transplantation and continued in the peri-transplantation period reduces the frequency
of these complications is yet to be systematically reviewed. It is reasonable to
suggest that the use of ERT prior to HSCT may alleviate disease manifestations, thus
reducing complications during HSCT. Whether long-term combined ERT and HSCT
may improve the outcome of a severely affected individual is of interest.
3. Substrate reduction therapy (SRT): Decreasing the quantity of stored substrate in
LSDs is currently being investigated for the treatment of Gaucher disease [96].
Potential use of similar molecules (genistein) that may decrease the production of
GAGs or other substances that are stored in MPS disease may have a future role in
treatment. A gene expression-targeted isoflavone therapy (GET-IT) is another,
though still experimental, option for treatment of MPS patients [97-98]. Nevertheless,
currently, some individual MPS I, II, IIIA and IIIB patients are treated worldwide by
SRT as an experimental therapy. This therapy is based on the use of genistein, a
naturally occurring isoflavone (4', 5, 7-trihydroxyisoflavone or 5, 7-dihydroxy-3-(4-
hydroxyphenyl)-4H-1-benzopyran-4-one), which indirectly impairs the efficiency of
GAG synthesis through inhibiting phosphorylation of epidermal growth factor
receptor, which results in impairment of the specific signal transduction process and
less efficient activation of expression of genes coding for some enzymes involved in
GAG production [99]. Slow GAG synthesis appears to prevent further accumulation
of these substances in patient’s cells, and residual activity of the deficient enzyme
may cause a reduction in the level of already accumulated compounds and
achievement of a new balance between GAG synthesis and degradation [100]. As
such, GET-IT is a specific case of SRT, which groups the treatment procedures
leading to impairment of production of compounds (substrates) that cannot be
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 20
efficiently degraded. The current dose of genistein used in human is 5 mg/kg daily.
In this dose, there is a limited effect in patients. Therefore, the optimal dose of
genistein must be explored carefully by monitoring genistein level in blood and
clinical effects. In MPS IIIB mouse model, to achieve the clear clinical effect, the
dose was increased to 160 mg/kg/day leading to a reversal of brain pathology and
complete correction of mouse cognitive behavior [101-102]. Importantly, no adverse
effects were observed in these mice even at doses as high as 160 mg/kg/day [101-
102]. Positive effects of genistein on brain were also observed in MPS II mice [103].
Moreover, a recent promising report on optimized reduction therapy (Substrate
Optimization Therapy) for HS could be applied to MPS I, II and III as well as MPS
VII [104-106].
4. RNA interference (RNAi): Another way to reduce GAG synthesis is the use of RNAi
phenomenon. This method appeared to be effective in cell culture experiments when
siRNA or shRNA were employed [107,108]. However, an efficient delivery of
specific RNA molecules to affected cells is still a problem in developing real
therapies for humans.
5. Non-steroid anti-inflammatory drug (NSAID) therapy: NSAID therapy by aspirin has
been experimentally performed on an MPS IIIA mouse model since pathways such as
inflammation or oxidative stress have been highlighted in many neurodegenerative
disorders, including LSDs as major contributors to the neuropathology (Figure 9).
Treatment with aspirin led to the normalization of inflammation and oxidative stress-
related mRNA levels, suggesting long term NSAID administration may be of
potential benefit in MPS III and other types of MPS in combination with ERT, gene
therapy and cell therapy [109].
Enzyme Replacement Therapy for Lysosomal Storage Diseases 21
Figure 9. Potential mechanism of pathogenesis for MPS and future therapeutic pathway involving autophagy,
inflammation, and ER stress. Primary storage material (GAG) triggers to accumulation of the secondary
products (GM2 ganglioside, GM3 ganglioside, disaloganglioside, subunit c of mitochondrial ATP synthase,
ubiuitin, and/or cholesterol), which affects the process of autophagy, inflammation, alteration of Ca++
homeostasis. 1) Lysosomal storage leads to a reduced ability of lysosomes to fuse with autophagosomes. 2)
This results in a block of autophagy maturation and defective degradation. 3) Consequently autophagy
substrates such as polyubiquitinated protein aggregates and dysfunctional mitochondria accumulate and
promote cell death. 4) The inflammatory response to cell damage further contributes to cell death [112,113].
By administering therapeutic agent which blocks the pathway or promote maturation of autophagosome, the
secondary accumulation or response will be reduced.
ERT has little effect in bone tissue, so treating the skeletal changes is one of the
objectives of new treatments. It was hypothesized that lysosomal and/or extracellular
GAG storage in MPS disorders induces inflammation and altered growth of connective
tissue and other cells through activation of Toll-like receptor 4 (TLR4) signaling pathway
[110]. Hyaluran fragments and oligosaccharides released from the breakdown of the
extracellular matrices also have been shown to signal through TLR4 providing further
support for the concept that GAG storage in MPS disorders activates this pathway. The
drug infliximab (Remicade®, Centocor Ortho Biotech, Inc) is an FDA-approved anti-
TNF-α drug which showed to attenuate the inflammatory response in MPS VI animals,
leading to improve joint pathology. The anti-inflammatory treatments should be
evaluated in MPS patients alone or associated with ERT due to the possibility of reducing
Lysosomal storage: primary and secondary
intracellular and extracellular locations
Defective autophagosome-lysosome
Impaired autophagosome maturation
Accumulation of toxic
proteins
Accumulation of aberrant
mitochondria
Cellular damage/distress
Inflammatory response,
ER stressEnhanced
apoptosis
Cell death
Tissue death(NO, IL-1β, TNF-α, TGF-β, MMP-2,
MMP-9, TIMP-1 )
Promote
maturation
Block (NSAID)
Block Block
Shunji Tomatsu, Adriana M. Montaño, Angela Catalina Sosa Molano et al. 22
inflammation, increase the accessibility of synovial tissues to recombinant proteins and
improve the efficacy of ERT.
6. Others: Moreover, lysosomes are organelles central to degradation and recycling
processes in animal cells. Most lysosomal genes exhibit coordinated transcriptional
behavior and are regulated by the transcription factor EB (TFEB). Under aberrant
lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus,
resulting in the activation of its target genes. TFEB overexpression in cultured cells
induced lysosomal biogenesis and increased the degradation of complex molecules,
such as GAGs in MPS IIIA mouse fibroblasts and neuronal stem cells. Thus, a
genetic program controls lysosomal biogenesis and function, providing a potential
therapeutic target to enhance cellular clearing in lysosomal storage disorders and
neurodegenerative diseases [111].
Figure 10. Scheme of therapy for MPS. Currently, ERT, HSCT and SRT are available in clinical practice for
MPS disorders. The decision about the appropriate modality of treatment depends on various factors,
including prognosis of the disease, the age of presentation, genotype/phenotype correlations when known, the
degree of organ involvement, the performance status of the patient at diagnosis, donor availability for HSCT,
and the availability and feasibility of ERT. Generally, in the case of the untreated symptomatic patients, ERT
and/or SRT should be the first option if available. It is reasonable to suggest that the use of ERT and/or SRT
prior to HSCT may alleviate disease manifestations, thus reducing complications during HSCT. Certainly for
HSCT to have any significant effect on CNS development, it should be done prior to age two years,
preferably earlier. If neurological and cognitive benefits are not expected, it is not indicative for HSCT.
When a newborn screening is established, prognosis should be carefully assessed prior to commencement of
therapy. .
Enzyme Replacement Therapy for Lysosomal Storage Diseases 23
IV. Conclusion
In the near future, we will have more therapeutic options in clinical practice in parallel
with establishment of newborn screening for MPS. It is hoped that physicians will take the
challenge to familiarize themselves with the most common symptom complexes, in order to
suspect the disease and to refer the patients to an expert center. Physicians also should know
therapies available on each type of MPS. It may be required to have tailored-made therapy for
each individual patient. Hopefully this will lead to more patients being diagnosed earlier on,
so adequate combination therapy can be provided and some irreparable damage can be
prevented. Not only ERT, gene therapy, HSCT and SRT but other supportive treatments
should be considered in combination (Figure 10).
It is unclear at present whether early diagnosis by newborn screening is beneficial from
the aspect of early initiation of ERT for CNS involved MPS since no effect of regular ERT on
children with the CNS form of the disease is anticipated. Consequently, SRT and/or ERT
combination therapy and HSCT as a permanent therapy will be considered when the
asymptomatic newborn is diagnosed.
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