Article:Enzyme replacement therapy: efficacy and limitations (6238252)
This page is the ScienceSource HTML version of the scholarly article described at https://www.wikidata.org/wiki/Q59340092. Its title is Enzyme replacement therapy: efficacy and limitations and the publication date was 2018-11-16. The initial author is Daniela Concolino.
Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.
Title: Italian Journal of Pediatrics
Enzyme replacement therapy: efficacy and limitations
- Daniela Concolino
- Federica Deodato
- Rossella Parini
Publication date (epub): 11/2018
Publication date (pmc-release): 11/2018
Publication date (collection): /2018
Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT.
Enzyme replacement therapy (ERT), based on the periodic intravenous administration of specific enzymes produced with recombinant DNA technology, is at present the most appropriate available therapy for several lysosomal storage disorders.
The recombinant enzymes are produced in continuous human (fibroblasts) or animal cell lines (Chinese hamster ovary (CHO) cells) and plant cells  and are a purified form of the lysosomal enzymes. The resulting glycoproteins present mannose-6-phosphate (M6P) residues on the oligosaccharide chains. This allows specific binding of the enzyme to M6P receptors on the cell surface, thus enabling the enzymes to enter the cell and to be targeted to lysosomes, with subsequent catabolism of accumulated substrates  (Fig. 1).Fig. 1
Mannose-6-phosphate (M6P) residues on the oligosaccharide chains of lysosomal enzymes are recognized by specific receptors present in the cell. Thanks to these receptors, the neo-synthesized enzymes are directed to the lysosomal compartment, where they perform their function. The M6P receptors are also expressed on the plasmatic membrane and this allows recombinant lysosomal enzymes to be “captured” by the cells and, following the pathway of the endocytic pathway, to be properly transported to the lysosome. Once lysosomes are reached, recombinant enzymes can replace the enzymatic deficit and degrade the accumulated substrate
The first effective treatment with ERT was performed in patients with Gaucher disease  and in the last 15 years ERT has become available for other lysosomal storage disorders including some types of mucopolysaccharidoses (MPS).
MPS I (Hurler, Hurler-Scheie, Scheie syndrome) was the first MPS type treated with ERT (available since 2003); subsequently the treatment became available for MPS VI (Maroteaux-Lamy syndrome; 2005), MPS II (Hunter syndrome; 2006), and MPS IVA (Morquio A syndrome; 2014) (Table 1). Recently, the recombinant enzyme β-glucuronidase has been tested for patients with MPS VII (Sly syndrome) [, ] and, to date, the treatment is available for commercial use in the United States where it was approved by the US Food and Drug Administration on 15 November 2017 (https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm585308.htm accessed on 27 June 2018) and is under review by the European Medicines Agency (EMA) (EMA/CHMP/181307/2018 Committee for medicinal products for human use (CHMP) Draft agenda for the meeting on 23–26 April 2018).Table 1
Enzyme replacement therapy (ERT) regimens for mucopolysaccharidoses (MPS)
|MPS I||MPS II||MPS IVA||MPS VI|
|Enzyme deficiency||α-l Iduronidase (IDUA)||Iduronate-2-sulphatase (IDS)||N-acetylgalactosamine-6-sulphatase (GALNS)||N-acetylgalactosamine-4-sulphatase (arylsulphatase B; ARSB)|
|Glycosaminoglycan accumulation||Dermatan sulphate and heparan sulphate||Dermatan sulphate and heparan sulphate||Keratan sulphate and chondroitin-6-sulphate||Dermatan sulphate|
|Drug||Laronidase (Aldurazyme®; Genzyme Europe B.V., Gooimeer 10, NL-1411 DD Naarden, The Netherlands), available since 2003||Recombinant human idursulphase (Elaprase®; Shire Human Genetic Therapies, Inc., Cambridge, MA, USA), available since 2006||Elosulphase alpha (Vimizim™; Bio Marin Pharmaceutical, Inc., Novato, CA, USA), available since 2014||Galsulphase (Naglazyme®; Bio Marin Pharmaceutical, Inc., Novato, CA, USA), available since 2005|
|Dosage||0.58 mg/kg body weight administered once every week as an intravenous infusion. The initial infusion rate of 10 μg/kg/h may be increased every 15 min, if tolerated, to a maximum of 200 μg/kg/h. The total volume of the administration should be delivered in approximately 3–4 h||0.5 mg/kg body weight administered once a week as intravenous infusions over 3 h. The duration of infusion can be shortened gradually to 1 h if there are no infusion-associated reactions (IARs)||2 mg/kg body weight administered once a week. The total volume of the infusion should be delivered over approximately 4 h||1 mg/kg body weight administered once a week as an intravenous infusion over 4 h|
|Official suggested premedication||With initial administration of Aldurazyme or upon re-administration following interruption of treatment due to previous IARs, pre-treatment with antihistamines and/or antipyretics approximately 60 min prior to the start of the infusion is recommended||Antihistamines and/or corticosteroids can be considered for those patients who have experienced previous IARs during the infusions||Patients should receive antihistamines with or without antipyretics 30 to 60 min prior to start of infusion||Antihistamines with or without antipyretics approximately 30–60 min prior to the start of infusion|
|Home treatment||Available||Available||Not available||Not available|
Results from clinical trials and the real-world setting confirm the efficacy and safety of ERT in the treatment of these multisystem, progressive disorders . The major proportion of the infused recombinant enzymes for MPS is delivered to the visceral organs such as the liver, kidney, and spleen [, ]. The infused enzymes have a short half-life in the circulation due to rapid binding to M6P receptors and uptake into visceral organs. It is known that only a small fraction of the recombinant enzyme can reach the bone cartilage and the eye, explaining why improvements of these organ/systems are limited even after long-term treatment [, ]. Moreover, due to the inefficacy of recombinant enzymes to cross the blood–brain barrier (BBB), there are no benefits of ERT for central nervous system (CNS) involvement [, ].
The ERT regimen for MPS requires weekly intravenous infusions of the recombinant enzyme. ERT is a life-long therapy, and each infusion takes 3 to 4 h depending on the enzyme and the dose (Table 1). There is the potential for severe infusion reactions; life-threatening anaphylaxis has rarely occurred in patients receiving ERT . Most infusions are given in a hospital setting because of this risk, but home infusions are reported to be feasible and safe for some patients and thus home treatment is now available for selected patients with MPS I and MPS II [, ]. The feasibility of home therapy for any MPS patient should be based on a risk/benefit evaluation by the treating physician, the patient, and the patient’s caregiver.
A comprehensive search of journal articles regarding safety and effectiveness of ERT in MPS I, MPS II, MPS IV, and MPS VI from 2003 to July 2017 was carried out on PubMed. The subject headings were Mucopolysaccharidosis I, Mucopolysaccharidosis II, Mucopolysaccharidosis IV, and Mucopolysaccharidosis VI, MPS I, MPS II, MPS IV, MPS VI, enzyme replacement therapy, ERT, laronidase and Aldurazyme, idursulfase and Elaprase, elosulfase and Vimizim, galsulfase and Naglazyme. They were used alone and in combination. All the results of the clinical trials are reported and commented upon, while only the most relevant and/or interesting (in our judgement) clinical studies were considered in this review.
Objectives of ERT
The various types of MPS have differences and similarities in their clinical pictures (see Galimberti et al.  and Rigoldi et al.  in this supplement) but we can generally say that the ideal aims of ERT are the same for all of them: reducing glycosaminoglycan (GAG) accumulation and organomegaly, improving growth (by ameliorating bone structure) and reducing bone deformities, improving the range of motion (ROM) of joints, and improving respiratory function, heart function, hearing, visual acuity, and quality of life (QoL). The major drawback of ERT molecules is their inability to cross the BBB and cure CNS pathology [, ].
What are the major effects and limits of ERT in MPS?
GAG and organomegaly
The demonstration that ERT is biochemically effective is given by the impressive fast decline of urinary GAG concentration (uGAG) over the first 3–6 months of administration followed by a slow continuous decline during the following years [–]. From the clinical point of view, a prompt reduction in liver and spleen volumes is observed after few months of therapy, which is subsequently maintained [–]; this effect was somehow expected from the beginning considering that tissue distribution studies in animals [, ] had shown very high uptake of the recombinant enzyme in the liver and spleen. Reduction in liver size may be relevant for the outcome of patients because it can directly help in improving respiratory function through facilitating diaphragm excursions.
In summary, ERT is very effective in reducing urinary GAG to approximately normal values and improving liver and spleen size. This effect is sustained over time.
One of the major complaints of patients affected by MPS I, II, and VI is joint stiffness which hampers the easy execution of normal activities of daily life (combing, bathing, dressing, putting a hat on the head). MPS IVA patients instead have joint laxity and other different disturbances such as pectus carenatum, wrist subluxation, early presentation of genu valgum, and frequent osteoarthritis in adults . Passive joint ROM improved in MPS I, II, and VI during clinical trials and improvement was maintained in the long term, although never reaching a normal extension/abduction of joints. Improvement is reported mainly for the shoulder, while the changes for the other joints have not been significant [, , , –]. The improvements in ROM were partial but allowed the accomplishment of many activities of daily living according to Sifuentes et al.  and Lampe et al. . Although the majority of the authors agree that ERT has an effect, albeit limited, on joint stiffness, other papers report no effect of ERT on joint limitations [, ].
In summary, the effect of ERT on joint movement is probably variable from one individual to another, partial even after many years of ERT, is limited to the shoulder and does not significantly affect the other joints. Furthermore, the different responses to therapy may be explained by different joint conditions at the start of ERT .
Heart involvement is typical of MPS. GAG deposition in the myocardium and cardiac valves is the first step of a complex pathway starting with the release of pro-inflammatory cytokines and matrix metalloproteinases consequently activating the macrophages that ultimately damage the tissues . While valve disease, when present at the start of ERT, is not reversible and progressively worsens, myocardial hypertrophy (or pseudohypertrophy) is responsive to ERT and the ejection fraction improves [, , , , ] (see also Boffi et al.in this Supplement ).
In summary, ERT improves the geometry and contraction of the cardiac muscle but has no clear effect on the valve structure.
Ear, nose, and throat, trachea, and pulmonary function
Ear, nose, and throat (ENT) disturbances are much frequent in MPS and consist of recurrent otitis and rhinosinusitis, tonsil and adenoid hypertrophy, sleep-related breathing disorders (oral breathing, snoring, obstructive sleep apnoea syndrome), and both conductive and sensorineural hearing loss [–]. Few data are reported about the effects of ERT on ENT signs and symptoms; ERT is acknowledged to reduce the number of upper airway infections and to improve sleep apnoea in the long term [, , , , ], mainly in patients with low-titre inhibitory antibodies . Tomanin et al. , however, showed no effect of ERT on sleep apnoea in MPS II. Besides this, ERT does not seem to be very effective in reducing tonsil and adenoid hypertrophy or hearing deficit [, , ].
Spirometric tests evaluating forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) (usually expressed as percent predicted FVC, or FVC%) have been used in clinical trials for all four MPS, showing improvements of 3–5% in the first year of treatment in MPS I and MPS IVA [, ]. For MPS II and MPS VI, FVC% did not significantly improve in double-blind trials [–]. In the long-term follow-up studies, results for FEV1 and FVC% range from stabilization to 11 ± 17% change from baseline [, , , ]. However, it seems that most patients probably reach a plateau after improvement at around 1–2 years of ERT and then stabilize or slowly progressively decline [, ]. The reason for this may be that ERT has effects only on one of the components responsible for airway insufficiency, which is multifactorial in MPS: GAG deposition in the soft tissues causes obstructive upper airway disease; tracheobronchial narrowing due to stenosis and malacia is responsible for obstructive lower airway disease; and chest deformities and poor mobility of the ribs lead to restrictive airway signs and symptoms. ERT is expected to be more effective on soft tissues and upper airway obstruction than on the other two factors. Chest deformities cannot be reverted, and the structure of the cartilaginous skeleton of the trachea and bronchi is likely to be marginally modified by the presently available ERTs . Two recent papers address in detail the issue of tracheal and bronchial narrowing in MPS patients [, ]. In many of these individuals, a severe tracheal collapse during expiration is seen and, the longer they survive, the more frequent become the complications of bronchial and tracheal stenosis and malacia. These deformities are frequently the basis of the severe obstructive respiratory symptoms of adult MPS patients, mainly MPS I, II, and VI, and a satisfactory treatment still needs to be found [, ].
In summary, ERT partially improves the functional capacity of the lung with great variability in different individuals; probably the improvement is limited to the first years of treatment, reaching a plateau. ERT has no effect on the anatomic structure of the trachea and bronchi which are narrow and tend to collapse during expiration.
Energy and endurance have been most commonly assessed in MPS-treated patients with the 6-min walk test (6MWT). Other tests of endurance are the 12MWT, used in the clinical trials for MPS VI, and the 3-min stair climb used in the trials for MPS VI and IV [, , ]. The 6MWT is a submaximal exercise tolerance test which includes evaluations of the responses and functional reserves of pulmonary, cardiovascular, and musculoskeletal systems . An improvement in the 6MWT was seen after short-term treatment in clinical trials and in long-term studies for all four MPS, although in the very long term it seems they reach a plateau [, , , , , , ].
However, both spirometry and 6MWT can be performed only in patients who are not too young or cognitively impaired; there are therefore categories of patients for whom these parameters cannot be applied.
In summary, tests of endurance are much suitable for testing improvements attributable to ERT in clinical trials because their results are seen early, a few months after starting treatment. Their improvement is sustained over the subsequent years. However, only patients with no cognitive impairment and who are not too young are able to undergo these tests.
Bones and growth
Bio-distribution of ERT in bones, articular, and growth cartilage is modest, probably mainly due to their poor vascular supply [, ]. No effect on skeletal deformities was shown in clinical trials [, , , ]; it is generally agreed that bone disease cannot be reversed or even stabilized by ERT .
As for growth, there are reports showing improvement of growth after ERT in MPS I, MPS II, and MPS VI [–], but this effect is usually limited unless the patient is treated from the first weeks or months of life. This has been demonstrated in familial case reports of affected siblings where the earlier treated siblings had less skeletal deformities and better growth than the first sibling [, –].
These family cases show that ERT may have an effect on growth and bone development if started very early. An improvement in growth during ERT has also been demonstrated in Morquio A patients under 5 years of age who were included in the open-label ERT MOR-007 trial .
In summary, the effect of ERT on bones and cartilage is limited, probably partially due to scarce penetration. However, a very early ERT start seems to improve bone health and growth as demonstrated by studies on siblings .
Eyes are frequently involved in the clinical picture of MPS. Corneal clouding is more often reported in MPS I, VI, and IVA, and optic disk swelling, optic atrophy, papilloedema, and retinal pigment degeneration in all . Few data are available on the efficacy of ERT. Stabilization and improvement of photophobia and, in some cases, improvement of visual acuity and reversal of papilloedema have been reported. It seems that if there are improvements, they are partial and possibly variable among individuals [, –].
In summary, some patients had an improvement in photophobia and visual acuity and other eye problems after ERT, but this is not observed in most patients.
Health-related quality of life (HRQoL)
The demonstration of biochemical and clinical improvements after ERT with all the assessments described above does not clarify if these effects really mean an improvement in QoL for patients and their families. Is it relevant for patients having a mild improvement in pulmonary function tests or in metres walked at the 6MWT? For the patients it is probably more relevant and meaningful to be more autonomous in performing activities of daily living (ADL), having less pain and satisfactory relationships with schoolmates or in the working environment. With the purpose of exploring this area, many studies have included the assessment of ADL, HRQoL, and pain in the parameters evaluated to demonstrate the efficacy of ERT. A recent review reports a critical comment on all the published studies and the different tests used . The most frequently used test was MPS-HAQ (CHAQ), an adaptation of the Health Assessment Questionnaire (HAQ)/Childhood Health Assessment Questionnaire (CHAQ) test used for rheumatoid arthritis . ADL and HRQoL were reported to improve after long-term ERT in MPS I patients who underwent clinical trials [, ]. The MPS-HAQ disability index improved after long-term ERT in cognitively normal MPS II patients [, ]. MPS-HAQ/CHAQ and pain control also improved in MPS IVA and MPS VI patients [, , , , , –]. However, the vast majority of the patients in these studies did not have cognitive delay. Demonstration of improvement in these parameters in the patients with CNS involvement (i.e. the most severe forms of MPS I and II) is lacking .
In summary, ERT is effective in improving ADL, HRQoL, and pain in those patients with no cognitive delay. We do not have enough data on the more severe patients with MPS I and II.
It is generally accepted that all the intravenous ERTs developed for MPS and other lysosomal storage diseases do not reach the CNS in amounts sufficient to prevent deterioration of CNS and neurocognitive functions [, , ]. This is particularly true for MPS I and MPS II, the MPS types with CNS involvement in the majority of the patients. The role of ERT in MPS I and MPS II severe phenotypes has been subject of debate [, ]. For MPS I, the main point is “when you should not offer HSCT to an MPS I Hurler patient balancing risks of HSCT with forecasted results?”
On the basis of the progressively reduced harm and mortality of HSCT in recent years, it is at present performed even beyond 2.5 years of age and in MPS I Hurler-Scheie patients who have a slower decline of cognitive functions [–]. For MPS II, the option of HSCT is not recommended at present, although a recent paper shows better results compared to ERT in a considerable number of patients . Most MPS II severe patients thus receive ERT from the diagnosis. The treatment is usually decided together with the family taking into consideration advantages for somatic organs and disadvantages related to possible infusion reactions and worsening of behavioural disturbances due to veni-puncture every week followed by 4-h infusion treatment. In our personal experience, only 2 of 19 families refused starting ERT in their children with a severe form of MPS II. This is consistent with the results of a survey conducted in MPS families where 77% of respondents were in favour of starting ERT in a patient with a severe phenotype, even knowing that treatment cannot alter the intellectual deterioration associated with the disease . At present, the opinion of the experts is that “withholding a therapeutic that has the potential to improve some of the somatic manifestations of the disease because of an eventual cognitive decline”, or even “if the cognitive decline is manifest”, “is not justifiable” . The response to ERT would be periodically assessed after starting treatment and, in case of apparent lack of clinical benefit, the decision to withdraw will then be discussed with the family .
In summary, ERTs developed for MPS and other lysosomal storage diseases do not reach the CNS in amounts sufficient to prevent deterioration of the CNS and neurocognitive function.
Safety and immunogenicity
Based on clinical trials, ERT for MPS is considered well tolerated and has an acceptable safety profile. Infusion adverse reactions (IAR), such as rash, urticaria, angioedema, bronchoconstriction, rhinitis, and anaphylaxis, have been reported in approximately 50% of MPS I patients treated with laronidase , approximately 30% of MPS II patients treated with idursulphase , approximately 90% of MPS IVA patients treated with elosulphase , and approximately 50% of MPS VI patients treated with galsulphase . The majority of IARs are usually mild and/or successfully treated by interrupting or slowing the rate of infusion and/or by the administration of anti-histamines, antipyretics and/or corticosteroids. Most patients who experience an IAR receive and tolerate subsequent infusions. Serious adverse reactions have been rarely reported such as anaphylaxis requiring emergency tracheotomy for an associated airway obstruction in a 16-year-old patient with MPS I Hurler-Scheie after 44 laronidase infusions . The reactions experienced during ERT can be caused by either IgE-mediated or non-immunological mechanisms. In the case of recurrent IARs, with failure of pre-medication to prevent hypersensitivity reactions, desensitization is indicated. Effective desensitization has been reported in patients affected by MPS I, MPS II, and MPS VI [, ].
Most ERTs used for treating lysosomal storage disorders produce an anti-drug antibody (ADA) response which can potentially reduce efficacy or lead to hypersensitivity reactions. The enzymes are taken up by antigen-presenting cells which process and present them to helper T cells specific for the generated peptide. Helper T-cell signals activate antigen-specific B cells to proliferate and differentiate into memory B cells, and into antibodies secreting plasma cells. ADAs may impair the desired biological effects of the therapeutic enzyme through several mechanisms, including altered enzyme targeting, increased enzyme turnover, and/or inhibition of the catalytic site. They can bind to segments of the therapeutic enzyme that are not associated with particular functional activities (non-neutralizing antibodies) or bind to the uptake or catalytic domains (neutralizing antibodies). The level and nature of the residual endogenous enzyme affects the propensity of the patient to generate ADAs. More than 90% of MPS I patients developed antibodies to laronidase during the first few months of treatment , about 50% of MPS II patients produced antibodies against idursulphase , and almost all patients treated with elosulphase  and galsulphase  produced ADAs. A clear correlation between ADA titre and clinical outcome has been shown in infantile-onset Pompe disease ; less is known about the role of immunogenicity in MPS, and the possible interference of antibodies with the efficacy of ERT is still unclear. A relationship between exposure to ADAs and a pharmacodynamic biomarker, uGAG, has been demonstrated in MPS I and MPS II. Some authors analysed the role of inhibitory antibodies on metabolic biomarkers and sleep disorders in ERT-treated MPS I patients. They showed that increasing inhibition of enzyme activity by antibodies correlated significantly with poorer substrate reduction .
A case of allo-immune membranous nephropathy has been reported in a patient with MPS VI treated with galsulphase. The finding of high titres of circulating ADA, which peaked at the onset of the nephrotic syndrome, indicates a mechanism of allo-immunization against the recombinant enzyme .
Undoubtedly, the effect of ADAs in MPS is more difficult to evaluate than in infantile Pompe disease due to the slowly progressive course of MPS and the fact that no consistent relationship between ADA titre and clinical outcome has been documented until now. A possible role of the time of uptake of the drug from the plasma into target cells via the M6P receptor, and therefore the mean plasma half-life of distinct ERT, has been recently hypothesized . Laronidase has a mean plasma half-life ranging from 1.5 to 3.6 h, while idursulphase, galsulphase, and elosulphase exhibit a mean plasma half-life of 44, 26, and 36 min, respectively. This rapid uptake may limit the drug’s exposure to antibodies in the plasma and might reduce the formation of immune complexes and their downstream effects.
Some attempts at immune tolerance induction in MPS patients treated with ERT have been performed. An open-label, phase II trial was undertaken to determine the safety and effectiveness of a prophylactic immunosuppressive regimen (cyclosporine and azathioprine) in treatment-naive patients with severe MPS I caused by two nonsense mutations . Unfortunately, the study was terminated early due to changing standards of care for this patient population with inconclusive results. An immune tolerance induction regimen similar to that used in infantile Pompe disease patients has been used in a 4-year-old MPS II patient with sustained high antibody titre and limited clinical efficacy of idursulphase treatment. Over 18 months, therapy with atumumab, bortezomib, methotrexate, short-term dexamethasone, and IVIG resulted in a significant reduction in neutralizing anti-idursulphase IgG titre and a moderate reduction in uGAG levels compared with baseline, while modest clinical improvements were observed .
Real-time access to ADA testing is not always easy in the clinical setting and the time to obtain assay results may reduce its clinical utility. However, the reader is reminded that ERT is a lifelong therapy for a devastating disease and that routine monitoring of ADAs is essential and should be part of the routine management of each patient on ERT.
Further prospective and more detailed investigations are needed to understand the real impact of the immune response to ERT and therefore the long-term safety and efficacy. Furthermore, more studies are needed to evaluate the type and the risk/benefit ratio of immunosuppressive therapy.
In summary, ERT for MPS is considered well tolerated and has an acceptable safety profile. However, the real impact of immune response on long-term efficacy remains to be elucidated.
Experience with ERT in MPS I, II, and VI is now reaching more than 10 years, while in MPS IVA the time of observation is shorter. As clearly reported in the literature, we could observe the benefits of this treatment in our patients in terms of reduction of organomegaly, improving pulmonary and heart function, and ameliorating HRQoL, but we also progressively realized that the patients had a big burden of “residual disease” accompanied by the need for several surgical treatments with increased risk of anaesthesia and bone and cartilage abnormalities which are not cured. This implies a risk of cord compression at any time and progressive tracheo-bronchomalacia with severe obstructive lower airway disease. Many patients develop antibodies to the recombinant enzyme and it is not clear yet if high-titre antibodies might influence the efficacy of the treatment with ERT .
The use of ERT in cognitively involved patients is a subject of debate and the most accepted position in the scientific community at present is that ERT should be started in any patient because it has the potential to improve some of the somatic manifestations of the disease .
Over the years we have also learned from many anecdotal familiar reports that ERT is much more effective, even on the bones, if administered very early. Since ERT is more powerful if it is started early, in a pre-symptomatic phase, new-born screening of treatable MPS has been proposed and pilot studies have been developed in many countries . Whether starting ERT at a very precocious age would be able to halt the progression of all the signs of the disease (excluding as usual the CNS) is not known. For certain, in the case of treatment of a pre-symptomatic or oligo-symptomatic patient, other ethical questions would arise, such as how to distinguish between severe and attenuated forms which might deserve different treatments (HSCT vs ERT for example). The elevated costs of these treatments complicate the choice.
Other drugs are at present being developed: different kinds of more powerful ERT, specifically targeting tissues such as bones where the disease is prominent, drugs based on different principles to enzyme replacement such as substrate deprivation, chaperone therapy, exon skipping, and gene therapy [, ]. We hope that all these research lines will develop good treatments for MPS to be used alone or associated with ERT.
The authors wish to thank the Italian MPS family Association ONLUS (AIMPS) and patients with their families. RP wishes to thank Fondazione Pierfranco and Luisa Mariani, Milano, for providing financial support for clinical assistance to metabolic patients and Mrs Vera Marchetti for her smart secretarial assistance to the clinical work at the Metabolic Unit in Monza.
The publication costs for this paper in the IJP supplement were made possible with unconditional financial support from BioMarin, Sanofi Genzyme, and Shire. The sponsors had no input into the content of articles, which were independently prepared by the authors and have undergone the journal’s standard peer-review process.
Availability of data and materials
About this supplement
This article has been published as part of Italian Journal of Pediatrics, Volume 44 Supplement 2, 2018: Mucopolysaccharidoses: state of the art. The full contents of the supplement are available online at https://ijponline.biomedcentral.com/articles/supplements/volume-44-supplement-2 .
- M RiesEnzyme replacement therapy and beyond—in memoriam roscoe O. Brady, M.D. (1923–2016)J Inherit Metab Dis20174034335610.1007/s10545-017-0032-828314976
- WS SlyReceptor-mediated transport of acid hydrolases to lysosomesCurr Top Cell Regul198526273810.1016/B978-0-12-152826-3.50010-33000696
- NW BartonFS FurbishGJ MurrayM GarfieldRO BradyTherapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher diseaseProc Nat AcadSci U S A1990871913191610.1073/pnas.87.5.1913
- JE FoxL VolpeJ BullaroED KakkisWS SlyFirst human treatment with investigational rhGUS enzyme replacement therapy in an advanced stage MPS VII patientMol Genet Metab201511420320810.1016/j.ymgme.2014.10.01725468648
- AM MontañoN Lock-HockRD SteinerBH GrahamM SzlagoR GreensteinClinical course of sly syndrome (mucopolysaccharidosis type VII)J Med Genet20165340341810.1136/jmedgenet-2015-10332226908836
- V ValayannopoulosFA WijburgTherapy for the mucopolysaccharidosesRheumatology (Oxford)201150Suppl 5v49v5910.1093/rheumatology/ker39622210671
- ED KakkisMF McEnteeA SchmidtchenEF NeufeldDA WardRE GompfLong-term and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis IBiochemMol Med19965815616710.1006/bmme.1996.0044
- CT TurnerJJ HopwoodDA BrooksEnzyme replacement therapy in mucopolysaccharidosis I: altered distribution and targeting of alpha-L-iduronidase in immunized ratsMol Genet Metab20006927728510.1006/mgme.2000.297910870845
- RM ShullED KakkisMF McEnteeSA KaniaAJ JonasEF NeufeldEnzyme replacement in a canine model of hurler syndromeProc Natl Acad Sci U S A199491129371294110.1073/pnas.91.26.129377809150
- WS SlyEnzyme replacement therapy: from concept to clinical practiceActa Paediatr2002439Suppl 91717810.1111/j.1651-2227.2002.tb03115.x
- DS AnsonC McIntyreS ByersTherapies for neurological disease in the mucopolysaccharidosesCurr Gene Ther20111113214310.2174/15665231179494079121291356
- LA ClarkeJE WraithM BeckEH KolodnyGM PastoresJ MuenzerLong-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis IPediatrics200912322924010.1542/peds.2007-384719117887
- F CeravoloI MascaroS SestitoE PascaleA LauricellaE DizioneHome treatment in paediatric patients with Hunter syndrome: the first Italian experienceItal J Pediatr2013395310.1186/1824-7288-39-5324011228
- J Cox-BrinkmanRG TimmermansFA WijburgWE DonkerAT van der PloegJM AertsHome treatment with enzyme replacement therapy for mucopolysaccharidosis type I is feasible and safeJ Inherit Metab Dis20073098410.1007/s10545-007-0686-817879143
- Galimberti C, Madeo A, Di Rocco M, Fiumara A. Mucopolysaccharidoses: early diagnostic signs in infants and children. Ital J Pediatr. 2018; 10.1186/s13052-018-0550-5.
- Rigoldi M, Verrecchia E, Manna R, Mascia MT. Clinical hints to diagnosis of attenuated forms of mucopolysaccharidosis. Ital J Pediatr. 2018; 10.1186/s13052-018-0551-4.
- M SifuentesR DoroshowR HoftG MasonI WalotM DiamentA follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 yearsMol Genet Metab20079017118010.1016/j.ymgme.2006.08.00717011223
- J MuenzerM BeckCM EngR GiuglianiP HarmatzR MartinLong term, open-labeled extension study of idursulfase in the treatment of hunter syndromeGenet Med2011139510110.1097/GIM.0b013e3181fea45921150784
- C LampeAK BosserhoffBK BurtonR GiuglianiCF de SouzaC BittarLong-term experience with enzyme replacement therapy (ERT) in MPS II patients with a severe phenotype: an international case seriesJ Inherit Metab Dis20143782382910.1007/s10545-014-9686-724596019
- R PariniM RigoldiL TedescoL BoffiA BrambillaS BertolettiEnzymatic replacement therapy for hunter disease: up to 9 years experience with 17 patientsMol Genet Metab Rep20153657410.1016/j.ymgmr.2015.03.01126937399
- R GiuglianiC LampeN GuffonD KetteridgeE Leão-TelesJE WraithNatural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)—ten year follow-up of patients who previously participated in an MPS VI survey studyAm J Med Genet A2014164A1953196410.1002/ajmg.a.3658424764221
- CJ HendrikszB BurtonTR FlemingP HarmatzD HughesSA JonesEfficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomized placebo-controlled studyJ Inherit Metab Dis20143797999010.1007/s10545-014-9715-624810369
- M KılıçA DursunT CoşkunA TokatlıRK ÖzgülD Yücel-YılmazGenotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from TurkeyAm J Med Genet A2017173112954296710.1002/ajmg.a.3845928884960
- ED KakkisE SchuchmanX HeQ WanS KaniaS WiemeltEnzyme replacement therapy in feline mucopolysaccharidosis IMol Genet Metab20017219920810.1006/mgme.2000.314011243725
- CJ HendrikszP HarmatzM BeckS JonesT WoodR LachmanReview of clinical presentation and diagnosis of mucopolysaccharidosis IVAMol Genet Metab2013110546410.1016/j.ymgme.2013.04.00223665161
- MMG BrandsE OussorenGJG RuijterAAM VollebregtHMP van den HoutKFM JoostenUp to five years experience with 11 mucopolysaccharidosis type VI patientsMol Genet Metab20139707610.1016/j.ymgme.2013.02.013
- T OkuyamaA TanakaY SuzukiH IdaT TanakaGF CoxJapan Elaprase treatment (JET) study: idursulfase enzyme replacement therapy in adult patients with attenuated hunter syndrome (mucopolysaccharidosis II, MPS II)Mol Genet Metab201099182510.1016/j.ymgme.2009.08.00619773189
- A Tylki-SzymanskaJ MaruchaA JureckaM SyczewskaB CzartoryskaEfficacy of recombinant human alpha-L-iduronidase (laronidase) on restricted range of motion of upper extremities in mucopolysaccharidosis type I patientsJ Inherit Metab Dis20103315115710.1007/s10545-010-9059-920217237
- HY LinCK ChuangCH WangYH ChienYM WangFJ TsaiLong-term galsulfase enzyme replacement therapy in Taiwanese mucopolysaccharidosis VI patients: a case seriesMol Genet Metab Rep20167636910.1016/j.ymgmr.2016.04.00327134829
- Boffi L, Russo P, Limongelli G. Early diagnosis and management of cardiac manifestations in mucopolysaccharidoses: a practical guide for paediatric and adult cardiologists. Ital J Pediatr. 2018; 10.1186/s13052-018-0560-3.
- NR GuaranyIV SchwartzFC GuaranyR GiuglianiFunctional capacity evaluation of patients with mucopolysaccharidosisJ Pediatr Rehabil Med20125374622543891
- EF NeufeldJ MuenzerCR ScriverAL BlaudetWS SlyD ValleThe mucopolysaccharidosesThe metabolic bases of inherited disease20018New YorkMcGraw Hill34213452
- JE WraithThe first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis IExpert Opin Pharmacother2005648950610.1517/146565188.8.131.52915794739
- F SantamariaMV AndreucciG ParentiM PolverinoD ViggianoS MontellaUpper airway obstructive disease in mucopolysaccharidoses: polysomnography, computed tomography and nasal endoscopy findingsJ Inherit Metab Dis20073074374910.1007/s10545-007-0555-517570075
- KI BergerSC FagondesR GiuglianiKA HardyKS LeeC McArdleRespiratory and sleep disorders in mucopolysaccharidosisJ Inherit Metab Dis20133620121010.1007/s10545-012-9555-123151682
- AR PalEJ LangereisMA SaifJ MercerHJ ChurchKL TyleeSleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcomeOrphanet J Rare Dis2015104210.1186/s13023-015-0255-425887468
- Ana Paula Fiuza Funicello DualibiAna Maria MartinsGustavo Antônio MoreiraMarisa Frasson de AzevedoReginaldo Raimundo FujitaShirley Shizue Nagata PignatariThe impact of laronidase treatment in otolaryngological manifestations of patients with mucopolysaccharidosisBrazilian Journal of Otorhinolaryngology201682552252810.1016/j.bjorl.2015.09.00626750310
- J MuenzerO BodamerB BurtonL ClarkeG Schulze-FrenkingR GiuglianiThe role of enzyme replacement therapy in severe hunter syndrome—an expert panel consensusEur J Pediatr201217118118810.1007/s00431-011-1606-322037758
- R TomaninA ZanettiF D’AvanzoA RampazzoN GasparottoR PariniClinical efficacy of enzyme replacement therapy in paediatric hunter patients, an independent study of 3.5 yearsOrphanet J Rare Dis2014912910.1186/s13023-014-0129-125231261
- DD HorovitzTS MagalhãesA AcostaEM RibeiroLR GiulianiDB PalharesEnzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VIMol Genet Metab2013109626910.1016/j.ymgme.2013.02.01423535281
- JE WraithL ClarkeM BeckEH KolodnyGM PastoresJ MuenzerEnzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human a-l-iduronidase (laronidase)J Pediatr200414458158810.1016/j.jpeds.2004.01.04615126990
- J MuenzerJE WraithM BeckR GiuglianiP HarmatzC EngA phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (hunter syndrome)Genet Med2006846547310.1097/01.gim.0000232477.37660.fb16912578
- M BeckJ MuenzerM ScarpaEvaluation of disease severity in mucopolysaccharidosesJ Pediatr Rehabil Med20103394621791828
- P HarmatzZF YuR GiuglianiIV SchwartzN GuffonEL TelesEnzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfataseJ Inherit Metab Dis201033516010.1007/s10545-009-9007-820140523
- CJ HendrikszKI BergerR PariniMD AlSayedJ RaimanR GiuglianiImpact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndromeJ Inherit Metab Dis20163983984710.1007/s10545-016-9973-627553181
- S KhanCJ Alméciga-DíazK SawamotoWG MackenzieMC TherouxC PizarroMucopolysaccharidosis IVA and glycosaminoglycansMol Genet Metab2017120789510.1016/j.ymgme.2016.11.00727979613
- M RuttenP CietR van den BiggelaarE OussorenJG LangendonkAT van der PloegandSevere tracheal and bronchial collapse in adults with type II mucopolysaccharidosisOrphanet J Rare Dis2016115010.1186/s13023-016-0425-z27112191
- C KampmannCM WiethoffRG HuthG StaatzE MengelM BeckManagement of life-threatening tracheal stenosis and tracheomalacia in patients with mucopolysaccharidosesJ Inherit Metab Dis Rep2017333339
- P HarmatzCB WhitleyL WaberR PaisR SteinerB PleckoEnzyme replacement therapy in mucopolysaccharidosis VI (Maroteaux-Lamy syndrome)J Pediatr200414457458010.1016/j.jpeds.2004.03.01815126989
- PL EnrightThe six-minute walk testRespir Care20034878378512890299
- P HarmatzR GiuglianiI SchwartzN GuffonEL TelesMC Sá MirandaEnzyme replacement therapy for mucopolysaccharidosis VI: a phase 3, randomized, double-blind, placebo-controlled, multinational study of recombinant human N-acetylgalactosamine 4-sulfatase (recombinant human arylsulfatase B or rhASB) and follow-on, open-label extension studyJ Pediatr200614853353910.1016/j.jpeds.2005.12.01416647419
- V Opoka-WiniarskaA JureckaA EmerykyA Tylki-SzymanskaOsteoimmunology in mucopolysaccharidoses type I, II, VI and VII. Immunological regulation of the osteoarticular system in the course of metabolic inflammationOsteoarthr Cartil2013211813182310.1016/j.joca.2013.08.00123954699
- JE WraithM BeckR LaneA van der PloegE ShapiroY XueEnzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-L-iduronidase (laronidase)Pediatrics2007120e37e4610.1542/peds.2006-215617606547
- R GiuglianiA FederhenMV RojasT VieiraO ArtigalasLL PintoMucopolysaccharidosis I, II, and VI: brief review and guidelines for treatmentGenet Mol Biol201033589e60410.1590/S1415-4757201000500009321637564
- P HarmatzEnzyme replacement therapy with galsulfase for mucopolysaccharidosis VI: clinical facts and figuresTurkish J Pediatr201052443e9
- S LarawayC BreenJ MercerS JonesEJ WraithDoes early use of enzyme replacement therapy alter the natural history of mucopolysaccharidosis I? Experience in three siblingsMol Genet Metab201310931531610.1016/j.ymgme.2013.04.02323721889
- NA Al-SannaaL BayDS BarbouthY BenhayounC GoizetN GuelbertEarly treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibshipsOrphanet J Rare Dis20151013110.1186/s13023-015-0344-426446585
- G TajimaN SakuraM KosugaT OkuyamaM KobayashiEffects of idursulfase enzyme replacement therapy for mucopolysaccharidosis type II when started in early infancy: comparison in two siblingsMol Genet Metab201310817217710.1016/j.ymgme.2012.12.01023375472
- O GabrielliLA ClarkeS BruniGV CoppaEnzyme-replacement therapy in a 5-month-old boy with attenuated presymptomatic MPS I: 5-year follow-upPediatrics2010125e183e18710.1542/peds.2009-172820026495
- O GabrielliLA ClarkeA FiccadentiL SantoroL ZampiniN Volpi12 year follow-up of enzyme-replacement therapy in two siblings with attenuated mucopolysaccharidosis I: the important role of early treatmentBMC Med Genet2016171910.1186/s12881-016-0284-426965916
- A Tylki-SzymanskaA JureckaZ ZuberA RozdzynskaJ MaruchaB CzartoryskaEnzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-upActa Paediatr2012101e42e4710.1111/j.1651-2227.2011.02385.x21672014
- JJ McGillAC InwoodDJ ComanML LipkeD de LoreSJ SwiedlerEnzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age—a sibling control studyClin Genet20107749249810.1111/j.1399-0004.2009.01324.x19968667
- SA JonesM BialerR PariniK MartinH WangK YangSafety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 yPediatr Res20157871772210.1038/pr.2015.16926331768
- J MuenzerEarly initiation of enzyme replacement therapy for the mucopolysaccharidosesMol Genet Metab2014111637210.1016/j.ymgme.2013.11.01524388732
- JL AshworthFE KruseB BachmannAP TormeneA SuppiejR PariniOcular manifestations in the mucopolysaccharidoses—a reviewClin Exp Ophthalmol201028122210.1111/j.1442-9071.2010.02364.x
- S PitzO OgunM BajboujL ArashG Schulze-FrenkingM BeckOcular changes in patients with mucopolysaccharidosis I receiving enzyme replacement therapy: a 4-year experienceArch Ophthalmol20071251353135610.1001/archopht.125.10.135317923542
- S PitzO OgunL ArashE MiebachM BeckDoes enzyme replacement therapy influence the ocular changes in type VI mucopolysaccharidosis?Graefes Arch Clin Exp Ophthalmol200924797598010.1007/s00417-008-1030-119159944
- CR FenzlK TeramotoM MoshirfarOcular manifestations and management recommendations of lysosomal storage disorders I: mucopolysaccharidosesClin Ophthalmol201591633164410.2147/OPTH.S7836826379420
- KT FahnehjelmJL AshworthS PitzM OlssonAL TörnquistP LindahlClinical guidelines for diagnosing and managing ocular manifestations in children with mucopolysaccharidosisActa Ophthalmol20129059560210.1111/j.1755-3768.2011.02280.x22136369
- S LarawayJ MercerE JamesonJ AshworthP HensmanSA JonesOutcomes of long-term treatment with laronidase in patients with mucopolysaccharidosis type IJ Pediatr201617821922610.1016/j.jpeds.2016.08.03327788836
- G SinghBH AthreyaJF FriesDP GoldsmithMeasurement of health status in children with juvenile rheumatoid arthritisArthritis Rheum1994371761176910.1002/art.17803712097986222
- P HarmatzM TreadwellBK BurtonJ MitchellN MuscholS JonesImpact of elosulfase alfa on pain in patients with Morquio syndrome type AMol Genet Metab2015114S51S5210.1016/j.ymgme.2014.12.104
- Christian J. HendrikszRoberto GiuglianiPaul HarmatzEugen MengelNathalie GuffonVassili ValayannopoulosRossella PariniDerralynn HughesGregory M. PastoresHeather A. LauMoeenaldeen D. Al-SayedJulian RaimanKe YangMatthew MealiffeChristine HallerMulti-domain impact of elosulfase alfa in Morquio A syndrome in the pivotal phase III trialMolecular Genetics and Metabolism2015114217818510.1016/j.ymgme.2014.08.01225284089
- Christian J HendrikszChristine LaveryMahmut CokerSema UcarMohit JainLisa BellChristina LampeBurden of disease in patients with Morquio A syndrome: results from an international patient-reported outcomes surveyOrphanet Journal of Rare Diseases2014913210.1186/1750-1172-9-3224602160
- P HarmatzD KetteridgeR GiuglianiN GuffonEL TelesMC MirandaDirect comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatasePediatrics2005115e681e68910.1542/peds.2004-102315930196
- RJ BoadoEK HuiJZ LuRK SumbriaWM PardridgeBlood–brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkeyBioconjug Chem2013241741174910.1021/bc400319d24059813
- MH de RuJJ BoelensAM DasSA JonesJH van der LeeN MahlaouiEnzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedureOrphanet J Rare Dis201165510.1186/1750-1172-6-5521831279
- JJ BoelensPJ OrchardRF WynnTransplantation in inborn errors of metabolism: current considerations and future perspectivesBr J Haematol201416729330310.1111/bjh.1305925074667
- M AldenhovenRF WynnPJ OrchardA O'MearaP VeysA FischerLong-term outcome of hurler syndrome patients after hematopoietic cell transplantation: an international multicenter studyBlood20151252164217210.1182/blood-2014-11-60807525624320
- MD PoeSL ChagnonML EscolarEarly treatment is associated with improved cognition in hurler syndromeAnn Neurol20147674775310.1002/ana.2424625103575
- F KubaskiH YabeY SuzukiT SetoT HamazakiRW MasonHematopoietic stem cell transplantation for patients with mucopolysaccharidosis IIBiol Blood Marrow Transplant201730551–7S1083S8791
- DJ ComanIM HayesV CollinsM SahharJE WraithMB DelatyckiEnzyme replacement therapy for mucopolysaccharidoses: opinions of patients and familiesJ Pediatr200815272372710.1016/j.jpeds.2007.10.01518410781
- BK BurtonDA WhitemanHunter Outcome Survey InvestigatorsIncidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS)Mol Genet Metab201110311312010.1016/j.ymgme.2011.02.01821439875
- P HarmatzR GiuglianiIV SchwartzN GuffonEL TelesMC MirandaJE WraithLong-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfataseMol Genet Metab20089446947510.1016/j.ymgme.2008.04.00118502162
- CD SerranoJF GomezSuccessful desensitization to idursulfase in a patient with type II mucopolysaccharidosis (hunter syndrome)J Investig Allergol Clin Immunol20112157157222312944
- H GuvenirE Dibek MisirliogluM CapanogluB BuyuktiryakiO UnalM ToyranCN KocabasSuccessful desensitization of elosulfase alfa-induced anaphylaxis in a pediatric patient with Morquio syndromeJ Allergy Clin Immunol Pract201751156115710.1016/j.jaip.2017.02.02028689831
- B LongT TompkinsC DeckerL JesaitisS KhanP SlasorLong-term immunogenicity of elosulfase alfa in the treatment of Morquio A syndrome: results from MOR-005, a phase III extension studyClin Thera201739118129.e310.1016/j.clinthera.2016.11.017
- MM BrandsM Hoogeveen-WesterveldMA KroosW NobelGJ RuijterL ÖzkanMucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfaseOrphanet J Rare Dis201385110.1186/1750-1172-8-5123557332
- SG BanugariaSN PraterJK NgJA KoboriRS FinkelRL LaddaThe impact of antibodies on clinical outcomes in diseases treated with therapeutic protein: lessons learned from infantile Pompe diseaseGenet Med20111372973610.1097/GIM.0b013e318217470321637107
- H DebiecV ValayannopoulosO BoyerLH NöelP CallardH SardaAllo-immune membranous nephropathy and recombinant arylsulfatase replacement therapy: a need for tolerance induction therapyJ Am Soc Nephrol201425467568010.1681/ASN.201303029024262793
- R GiuglianiTA VieiraCG CarvalhoMV Muñoz-RojasAN SemyachkinaVY VoinovaImmune tolerance induction for laronidase treatment in mucopolysaccharidosis IMol Genet Metab Rep201710616610.1016/j.ymgmr.2017.01.00428119821
- KH KimYH MessingerBK BurtonSuccessful reduction of high-sustained anti-idursulfase antibody titers by immune modulation therapy in a patient with severe mucopolysaccharidosis type IIMol Genet Metab Rep20152202410.1016/j.ymgmr.2014.11.00728649520
- LA ClarkeAM AthertonBK BurtonDL Day-SalvatoreP KaplanND LeslieCR ScottMucopolysaccharidosis type I newborn screening: best practices for diagnosis and managementJ Pediatr201718236337010.1016/j.jpeds.2016.11.03627939258
- I NestrasilE ShapiroA SvatkovaP DicksonA ChenA WakumotoIntrathecal enzyme replacement therapy reverses cognitive decline in mucopolysaccharidosis type IAm J Med Genet A201717378078310.1002/ajmg.a.3807328211988
- R GiuglianiA FederhenF VairoC VanzellaG PasqualimLM da SilvaEmerging drugs for the treatment of mucopolysaccharidosesExpert Opin Emerg Drugs20162192610.1517/14728214.2016.112369026751109