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Pharmacokinetic profile of recombinant human N-acetylgalactosamine 4-sulphatase enzyme replacement therapy in patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): A phase I/II study
Abstract
Aim: Mucopolysaccharidosis VI (Maroteaux–Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulphatase (ASB). Enzyme replacement therapy with recombinant human ASB (rhASB) has been studied in a randomized, double-blind, two-dose (0.2 and 1.0 mg/kg/week) phase I/II study (n=7) followed by an open-label single dose (1.0 mg/kg/week) extension study. We report the pharmacokinetic profile of rhASB and the impact of antibody development. Methods: Pharmacokinetic analysis was performed at weeks 1, 2, 12, 24, 83, 84 and 96. Infusions were administered over 4 hours using a ramp-up protocol. Plasma ASB and rhASB antibody concentrations and urine glycosaminoglycan (GAG) concentrations were determined. Results: The area under the plasma concentration–time curve (AUC0−t) for the high-dose group increased from week 1 to week 2, but remained unchanged at weeks 12 and 24. A large difference in mean AUC0−t was observed between the low- and high-dose groups. Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. Six patients developed antibodies to rhASB. One patient developed high antibody levels in combination with a high ASB concentration, while a second patient also developed high antibody levels with undetectable ASB concentrations. Antibodies from the second patient blocked detection of ASB. By week 72, antibody levels had decreased in all patients. The high-dose rhASB produced a more rapid and greater percentage reduction in urinary GAG concentrations than the lower dose (70% versus 55% at 24 weeks). Antibody levels did not appear to influence urinary GAG concentrations.
... Antigen was not measurable in the plasma within 10 min after the completion of the enzyme infusion in all patients. rhASB pharmacokinetics appeared to be nonlinear, as reflected by greater than dose-proportionate increases in AUC 0-t ( Figure 1) [4,20]. AUC 0-t increased relative to week 1 values in the high-dose patients, but remained unchanged in the low-dose patients. ...
... Pharmacokinetic results at weeks 83, 84 and 96 were similar to those at week 24. The high-dose rhASB led to a more rapid and greater reduction in uGAG concentrations than the lower dose (70 vs 55% at 24 weeks) [4,20]. ...
... Study drug was given once per week as a 4-h i.v. infusion [4,20]. ...
Introduction: Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive lysosomal storage disorder caused by a deficiency in the lysosomal enzyme N-acetylgalactosamine 4-sulfatase (arylsulfatase B), leading to an accumulation of glycosaminoglycans within lysosomes. MPS VI patients experience a progressive, chronic and multisystemic disease that causes not only significant morbidity but also early mortality. Areas covered: Galsulfase, a recombinant human N-acetylgalactosamine 4-sulfatase, rhASB (Naglazyme®), is produced by recombinant DNA technology in a CHO-derived cell line, and was approved in the US (2005) and the EU (2006) for use in MPS VI patients. The authors examine the published pharmacokinetic, safety and efficacy data from the Phase I/II, Phase III, Phase III extension, post-marketing surveillance studies of galsulfase, published case reports and cohort of patients treated with rhASB. Expert opinion: Galsulfase is generally well tolerated, having an acceptable safety profile. Few infusion reactions have occurred during administration of galsulfase, being generally mild-to-moderate in severity. Improvements in 12-minute walk test, nearly significant improvement in 3-min stair climb and significant reduction in urinary GAG levels were demonstrated in the 24-week, randomized, double-blind Phase III trial that led to the approval of the drug. As in other lysosomal storage diseases, the antibody response to enzyme replacement therapy can differ greatly between patients and may to some extent relate to the genotype. Nevertheless, antibody formation seems to have little impact on clinical outcome in MPS VI patients treated with galsulfase.
... ERT reduces visceral lysosomal storage, and normalizes the pathological phenotype in peripheral organs. One of the two clinically approved therapeutic options in MPS treatment, ERT was initially developed by Barton et al. (1991) as a treatment for Gaucher's disease and, following its success, has since been adapted to treat a number of MPS subtypes, including MPS I, MPS II, MPS IVA, MPS VI, and MPS VII [20,[35][36][37][38][39][40]. Fundamentally, ERT consists of semi-weekly intravenous infusions of the deficient lysosomal enzyme. ...
... This is showcased by a phase 3, randomized, double-blind, placebo-controlled clinical trial conducted by Harmatz et al. investigating the potential of recombinant human arysulfatase B (rhASB) as a replacement enzyme to treat MPS VI. In this study, researchers found that patients receiving weekly intravenous rhASB infusions exhibited a significant increase in walking distance in the 12-min walk test and a significant decrease in urinary GAG levels compared to patients given a placebo [38]. The improvements in measures of systemic lysosomal clearance and endurance show that rhASB based ERT indeed has the potential to be an effective treatment for the peripheral component of MPS VI, however, a major drawback of this therapy is its inability to cross the BBB and the resulting neglect of the neurological aspect of the disease. ...
Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight clinically distinct types of mucopolysaccharidosis, some with various subtypes, based on which lysosomal enzyme is deficient and symptom severity. Patients with mucopolysaccharidosis can present with a variety of symptoms, including cognitive dysfunction, hepatosplenomegaly, skeletal abnormalities, and cardiopulmonary issues. Additionally, the onset and severity of symptoms can vary depending on the specific disorder, with symptoms typically arising during early childhood. While there is currently no cure for mucopolysaccharidosis, there are clinically approved therapies for the management of clinical symptoms, such as enzyme replacement therapy. Enzyme replacement therapy is typically administered intravenously, which allows for the systemic delivery of the deficient enzymes to peripheral organ sites. However, crossing the blood–brain barrier (BBB) to ameliorate the neurological symptoms of mucopolysaccharidosis continues to remain a challenge for these large macromolecules. In this review, we discuss the transport mechanisms for the delivery of lysosomal enzymes across the BBB. Additionally, we discuss the several therapeutic approaches, both preclinical and clinical, for the treatment of mucopolysaccharidoses.
... Based on these data, weekly 4-h infusions have been used clinically to permit greater distribution of rhASB to distal connective tissues [2]. When the infusion rate was adjusted so that approximately 2.5% of a 1 mg/kg dose of rhASB was infused during the first hour and the remaining 97.5% was infused over the next 3 h, high plasma rhASB concentrations were maintained over the final 3-h infusion period and the plasma half-life ranged from 120 to 180 min [4]. Several clinical trials with rhASB have confirmed the efficacy of this 4-h dosing schedule for the treatment of patients with MPS VI [5][6][7]. ...
... This reduces the tissue exposure with the enzyme in distal tissues. Animal and human pharmacokinetic and biodistribution ERT data for both MPS I and MPS VI indicate a 4-h infusion is optimal to sufficiently saturate mannose-6-phosphate receptors for adequate enzyme uptake and to allow sufficient time for delivery of enzyme to distal and difficult to reach connective tissues [3,4,6,[23][24][25]. Animal studies demonstrate that concentrations of enzyme delivered above saturation levels results in disproportionately more circulating enzyme delivered to the liver rather than to distal connective tissues [3,23,26,27]. ...
... Based on these data, weekly 4-h infusions have been used clinically to permit greater distribution of rhASB to distal connective tissues [2]. When the infusion rate was adjusted so that approximately 2.5% of a 1 mg/kg dose of rhASB was infused during the first hour and the remaining 97.5% was infused over the next 3 h, high plasma rhASB concentrations were maintained over the final 3-h infusion period and the plasma half-life ranged from 120 to 180 min [4]. Several clinical trials with rhASB have confirmed the efficacy of this 4-h dosing schedule for the treatment of patients with MPS VI [5][6][7]. ...
... This reduces the tissue exposure with the enzyme in distal tissues. Animal and human pharmacokinetic and biodistribution ERT data for both MPS I and MPS VI indicate a 4-h infusion is optimal to sufficiently saturate mannose-6-phosphate receptors for adequate enzyme uptake and to allow sufficient time for delivery of enzyme to distal and difficult to reach connective tissues [3,4,6,[23][24][25]. Animal studies demonstrate that concentrations of enzyme delivered above saturation levels results in disproportionately more circulating enzyme delivered to the liver rather than to distal connective tissues [3,23,26,27]. ...
Background:
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease characterized by an absence or marked reduction of lysosomal N-acetylgalactosamine-4-sulfatase activity. Affected individuals have widespread accumulation of unmetabolized glycosaminoglycan substrates leading to detrimental effects. Recombinant human N-acetylgalactosamine 4-sulfatase (rhASB) is an approved enzyme replacement therapy for patients with MPS VI. Despite the known efficacy of weekly 4-h rhASB infusions, some clinicians wish to treat patients using reduced infusion times. This study compared the pharmacodynamics, pharmacokinetics, and tissue biodistribution of rhASB when administered as 2- and 4-h intravenous infusions using a feline model of MPS VI.
Methods:
Study animals were MPS VI-affected cats that demonstrate clinical signs and biochemical derangements similar to human MPS VI patients. Beginning at age 4weeks, animals received weekly 2-h (N=6) or 4-h (N=6) IV infusions of rhASB for 26weeks (Naglazyme® [galsulfase] Solution for Intravenous Infusion; BioMarin Pharmaceutical, Inc.). The control group consisted of untreated MPS VI-affected cats (N=6). The pharmacokinetic parameters of plasma rhASB and urinary glycosaminoglycan were determined at weeks 13 and 26. Animals were euthanized 48h after the last infusion and tissue concentration of ASB, GAG and β-glucuronidase were measured in the liver, spleen, aorta, and kidney. Skeletal and ophthalmological evaluations were performed within 2weeks of euthanasia.
Results:
At week 13, the mean AUC0-t in animals treated with 4-h infusions was similar to 2-h infusions while the Cmax of the 4-h infusion was 50% of the 2-h infusion. By week 26, the mean AUC0-t of the 4-h infusion was 1.3-fold higher than the 2-h infusion (p<0.05) while Cmax of the 4-h infusion was 70% of the 2-h infusion (p<0.05). Among animals treated with 2- and 4-h infusions, there was no difference in urinary GAG excretion, tissue GAG storage, tissue galsulfase activity, and β-glucuronidase but all were significantly different than control animals (for each, p<0.001). Radiographic skeletal abnormality scores for animals were also similar for both treatment groups and significantly higher than control animals (p<0.001). There was no significant difference in corneal clouding scores among treated and untreated animals.
Conclusions:
There was no significant difference in clinical outcomes when rhASB was administered to MPS VI affected cats as 2- and 4-h infusions over 26weeks. Additional studies may determine if shorter infusion times are appropriate for MPS VI patients without significant infusion-associated reactions.
... 3 The enzyme replacement therapy (ERT) with galsulfase has been approved by the Food and Drug Administration and the European Medicines Agency (EMA) for the treatment of MPS VI in 2005 and 2006, respectively. 4 The aim of this study was to report the evolution of a patient with MPS VI after 2 years of treatment with ERT and cervical decompression surgery. ...
... The benefit in the functional motor scales 6MWT and 3MCS seen in our patient resembles the results previously described in phase III, which led to the final approval of ERT. 4 Cardiac improvement in our patient is made evident by the stabilization of LVMI and of parietal thickness with significant decrease in the end-diastolic diameter. The systolic function of the LV remained normal with 59% ejection fraction. ...
Introduction:
Mucopolysaccharidosis VI (MPS VI) is the result of the absence of arylsulfatase B leading to the abnormal lysosomal accumulation of glycosaminoglycans. Two different phenotypes have been described to date, namely, rapidly progressive and slowly progressive.
Aim:
To present the evolution of a slowly progressive phenotype of MPS VI in a patient after 2 years of enzyme replacement therapy.
Case report:
A 26-year-old man diagnosed with MPS VI at 9 years of age started enzyme replacement therapy with galsulfase due to cardiac, pulmonary, neurologic, and joint involvement. After 10 months of treatment, improvement in quality-of-life scales and walk test was evident. Because of persistent symptomatology associated with narrow cervical spinal canal, decompressive surgery was performed. After 2 years of treatment, there was a clear improvement in the respiratory, motor, and cardiac functions as well as in the spinal symptoms.
Discussion:
The evolution of our patient leads to the conclusion that the combined treatment of galasulfase and decompressive surgery should be indicated at an early stage in order to achieve best outcome for the patient.
... Two studies (3 publications) which met the minimal methodological requirements were included in the review. [10][11][12] included studies Two studies (3 publications) were included in this review [10][11][12] with a total of 46 participants. ...
... Two studies (3 publications) which met the minimal methodological requirements were included in the review. [10][11][12] included studies Two studies (3 publications) were included in this review [10][11][12] with a total of 46 participants. ...
... First, almost all MPS VI patients treated with ERT develop antibodies to rhARSB independently of their genotypes or disease severity. 4,23,[38][39][40] Nevertheless, they experience clinical benefits under ERT. 4,[38][39][40] In addition, liver-directed gene therapy has been demonstrated to either prevent the generation of humoral immunity 18 or to eradicate it, if already present, 19,20 which makes the impact of preexisting humoral immunity to the transgene product on gene therapy efficacy difficult to predict. ...
... 4,23,[38][39][40] Nevertheless, they experience clinical benefits under ERT. 4,[38][39][40] In addition, liver-directed gene therapy has been demonstrated to either prevent the generation of humoral immunity 18 or to eradicate it, if already present, 19,20 which makes the impact of preexisting humoral immunity to the transgene product on gene therapy efficacy difficult to predict. Therefore, there is a good argument for not excluding neither patients with preexisting immunity to rhARSB nor ARSB CRIM-negative patients from the trial. ...
Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Pre-existing immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for Mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder due to arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. The detection of ARSB protein in twenty-four patients out of 34 (71%) was predicted by the type of mutations. Pre-existing Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8.
... Um dos parâmetros mais utilizados na literatura, o da American Thoracic Society (ATS), considera o ponto de corte de 54m (IC95%: 37-71) como clinicamente significativo 22 . A metanálise realizada neste artigo, ao comparar os efeitos pré-e pós-tratamento, demonstrou que a IDS foi capaz de aumentar a distância percorrida no TC 6min em 43,5m (IC95%: 25,9), porém as modificações médias não foram clinicamente relevantes. ...
... A mobilidade articular não foi avaliada satisfatoriamente após a TRE, seja por dificuldades metodológicas de aferição, seja pela heterogeneidade clínica, seja pela amplitude etária dos pacientes envolvidos. Não encontramos na literatura quais seriam os valores considerados clinicamente relevantes, mas alguns autores, avaliando MPS VI, consideram arbitrariamente o aumento superior a 10 o como significativo 25,26 . Portanto, houve mudanças clinicamente relevantes na mobilidade articular do cotovelo (diferença média não relatada) 13 , ombro (aproximadamente 12 o , abdução, flexão-extensão) 16 e quadril (aproximadamente 14 o , flexão), este último avaliado apenas por um pequeno estudo (n = 10 pacientes) 15 . ...
Mucopolysaccharidosis type II (MPS II) is a genetic disease of broad clinical spectrum, characterized by a deficiency of the enzyme iduronate2-sulfatase. The aim of this study was to assess whether enzyme replacement therapy (ERT) with idursulfase (IDS) for MPS II is effective and safe. PubMed/MEDLINE, Embase, LILACS, and Cochrane Library were searched until November 30, 2012. Only five articles met the inclusion criteria (randomized controlled trials RCTs, or open-label trials/prospective case series including > 5 patients and evaluating relevant outcomes). A meta-analysis was performed for forced vital capacity (FVC; absolute and %) and for distance walked on the 6-minute walking test (6MWT). There was a statistically significant increase, but not clinically relevant, in both variables; an increased risk for development of mild infusion-related reactions and IgG antibodies to IDS were also found. The data suggest that ERT with IDS is safe and has a potential benefit for MPS II patients, but further studies are required.
... The results of our study are in line with those published on the pivotal clinical trials of mucopolysaccharidosis type VI patients [8,17,18]. One important difference is that our study includes three children under 5 years of age at start of therapy. ...
... Consequently, our patients were generally younger, with a median of 6.8 years (2-18.3 years) against the phase-I median age of 11 years (range 7-16 years), the phase-II median age of 12.0 years (range 6-22 years), and the phase-III treatment-group median age of 12.0 years (range 8-29 years) [8,17,18]. Our median follow-up time (3.7 years; range 1.3-5.4 ...
... As a consequence, dermatan sulphate and chondroitin sulphate accumulate within the lysosomes of the connective tissue cells within most organs [1]. If a compatible donor is available, bone marrow transplantation can be considered as a therapeutic option for affected children [2][3][4], however, evidence now indicates that intravenous enzyme replacement therapy (IV ERT) with recombinant human 4-sulphatase (rhASB) can be a safer alternative offering short-term and longer-term benefits [5][6][7][8][9][10]. ...
... MPS-VI patients are expected to develop antibodies towards rhASB during the course of therapy since many patients have no residual rhASB protein in their system and are unlikely to have received IV ERT from a very early age [30]. Indeed clinical studies in MPS-VI patients receiving weekly IV ERT with rhASB showed that all patients had seroconverted by 30 weeks of treatment [6,8,10]. Therefore, inducing a state of immunotolerance towards rhASB might also benefit MPS-VI patients by eliminating the possibility of anti-rhASB antibody interference with therapy and by preventing development of hypersensitivity reactions. ...
All MPS-VI cats treated thus far with weekly intravenous enzyme replacement therapy (IV ERT) with recombinant human N-acetylgalactosamine-4-sulphatase (rhASB) from 3 months of age onwards developed circulating anti-rhASB antibodies. In view of this, the possibility of inducing immune tolerance by using a short-course tolerisation regimen was tested. Starting at 4 months of age, MPS-VI (n=5) and unaffected cats (n=2) received cyclosporine and azathioprine over a 22-day period plus weekly IV ERT with 0.1mg/kg rhASB. After a 4-week resting period, these cats were administered weekly IV ERT with 1mg/kg rhASB until 11 or 17 months of age. Four unaffected cats (n=4) received weekly IV ERT only. Health, growth and seroconversion were regularly monitored. Four out of five MPS-VI cats tolerated rhASB well, as indicated by negligible or low antibody titres and absence of hypersensitivity reactions. One MPS-VI cat exhibited elevated antibody titres and hypersensitivity reactions during some IV treatments. The two unaffected cats that received the tolerisation regimen remained seronegative, however, only half of the unaffected cats not submitted to this regimen seroconverted. Only minor side-effects were attributed to the short-course of cyclosporine and azathioprine. Two MPS-VI cats also well-tolerated four weekly intrathecal injections of rhASB and consequently exhibited less oligosaccharide fragments in cerebrospinal fluid and less vacuolation within their dura mater. These data indicate that a relatively high rate of immunotolerance towards rhASB can be achieved in MPS-VI cats with a short-course tolerisation regimen ultimately permitting removal of lysosomal storage within the dura mater with the use of intrathecal therapy.
... Enzyme replacement therapy (ERT) with galsulfase has been available to treat MPS VI since 2005 in the United States and 2006 in Europe. Results from clinical trials demonstrate that ERT improves walking ability, endurance, and pulmonary function [5][6][7]. However, ERT is not curative and fails to resolve many pathological changes, in particular when present prior to initiation of therapy with ERT [8]. ...
Mucopolysaccharidosis type VI (MPS VI) is an autosomal recessive lysosomal storage disorder characterized by deficient activity of arylsulfatase B enzyme (ASB) resulting in cellular accumulation of dermatan sulfate (DS) and chondroitin sulfate (CS) that leads to cell injury. Urinary glycosaminoglycans (GAG) are often used as a biomarker in MPS diseases for diagnosis and to monitor treatment efficacy. This study evaluated leukocyte GAGs (leukoGAG) and skin GAGs as alternate biomarkers representing intracellular GAG changes in patients with MPS VI and treated with enzyme replacement therapy (ERT). In addition, we evaluated corneal opacification measurements (COM) and carotid intima media thickness (CIMT) as indicators of GAG accumulation and tissue injury. The study was performed in a serial two-step design in a single center. A quantitative method to measure leukoGAG levels in leukocytes was developed in Study 1 to compare the GAG levels between MPS VI patients and a control group and to assess correlations between leukoGAG and urineGAG. Study 2 validated the leukoGAG measurement, assessed the effect of ERT infusion on leukoGAG and ASB activity in leukocytes, identified correlations between leukoGAG and other biomarkers, and assessed differences in GAG accumulation between MPS VI patients and control subjects. In Study 1, leukoCS and leukoDS levels were significantly higher in the MPS VI group than the control group (leukoCS: 37.9 ± 10.2 and 2.9 ± 1.5 μg/μg protein, respectively, p = 0.005; leukoDS: 0.26 ± 0.2 and 0.0 ± 0.0 μg/μg protein, respectively, p = 0.028) with positive correlations between leukoCS and urine CS and leukoDS and urineDS. In Study 2, leukoCS (32.0 ± 11.8 vs 6.9 ± 3.1 μg/mg protein, p = 0.005) and leukoDS (0.4 ± 0.1 and 0.2 ± 0.1 μg/mg protein, p = 0.020) were significantly higher compared with control subjects. Thus, these results highlight the potential of leukoGAG as a new biomarker representing intracellular GAG accumulation in MPS VI patients and may be valuable for patient management.
... 2 In the clinic, soluble lysosomal hydrolases are available in recombinant form for some types of lysosomal storage disease, and may be delivered by repeated infusion into the bloodstream or into the cerebrospinal fluid. [3][4][5][6][7][8][9] However, no therapeutic options are currently approved for Sanfilippo syndrome. ...
Recombinant human alpha- N -acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. Because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated, we generated a fusion protein of NAGLU with IGF2 to permit its binding to the cation-independent mannose 6-phosphate receptor. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice, and demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied intracerebroventricular rhNAGLU-IGF2 delivery in both murine and canine Sanfilippo B to determine potential effects on their behavioral phenotypes and survival. Treated mice showed improvement in disease markers such as heparan sulfate glycosaminoglycans, beta-hexosaminidase, microglial activation, and lysosomal-associated membrane protein-1. Sanfilippo B mice treated with rhNAGLU-IGF2 displayed partial normalization of their stretch attend postures, a defined fear pose in mice (p<0.001). We found a more normal dark/light activity pattern in Sanfilippo B mice treated with rhNAGLU-IGF2 compared to vehicle-treated Sanfilippo B mice (p=0.025). We also found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53w, median 48w) compared to vehicle-treated Sanfilippo B mice (mean 33w, median 37w; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized HS and beta-hexosaminidase activity in gray and white matter brain regions. Proteomic analysis of cerebral cortex showed restoration of protein expression levels in pathways relevant to cognitive function, synapse, and the lysosome. These data suggest that treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.
... The use of growth hormones produces encouraging results on the development [14]. The genetic therapy is still at the experimental stage similarly to the substitutive enzymotherapy and the cathepsin K inhibitors used in the treatment against osteoporosis [15][16][17]. Most of the treatment primarily bears a preventive aim with an early screening and a regular monitoring of the fractures, which strengthening is often slowed down. ...
... The impact of ADA on PK has been investigated for other ERTs and different results have been reported [20,[22][23][24]. The impact of antibodies on the PK appears to be variable according to the therapeutic protein considered. ...
Introduction
Mucopolysaccharidosis type VII (MPS VII, Sly Syndrome) is a progressive, debilitating, ultra-rare lysosomal storage disorder caused by the deficiency of β-glucuronidase (GUS), an enzyme required for breakdown of glycosaminoglycans (GAGs). Vestronidase alfa, a recombinant human GUS, is an enzyme replacement therapy approved in the US and EU for the treatment of MPS VII.
Methods
The pharmacokinetics (PK) and pharmacodynamics (PD) of vestronidase alfa were evaluated in 23 adult and pediatric subjects with MPS VII enrolled in phase I–III clinical trials to optimize the clinical dosing regimen of vestronidase alfa. The serum concentration-time profiles were adequately described by a two-compartment population PK model incorporating subjects’ body weight as the only significant covariate.
Results
Model-based simulations predicted a substantially decreased time duration of serum exposures exceeding the level of Kuptake (the in vitro determined vestronidase alfa concentration corresponding to 50% maximum rate of cellular uptake) for 4 or 8 mg/kg once every 4 weeks dosing, compared with 4 mg/kg once every other week (QOW) dosing by intravenous infusion, suggesting that given the same total monthly dose, the QOW dosing frequency should result in more efficient delivery to the GUS-deficient tissue cells, and therefore superior treatment efficacy. A standard inhibitory maximal effect model reasonably explained the observed pharmacological PD responses of reduction in urinary GAGs from pretreatment baseline, which appeared to have reached the plateau of maximal effect at the 4 mg/kg QOW dose.
Conclusion
The modeling results, together with the clinical evidence of safety and efficacy, supported the recommended 4 mg/kg QOW dosing regimen of vestronidase alfa for pediatric and adult patients with MPS VII.
Clinical Trial Registration
NCT01856218, NCT02418455, NCT02230566.
... However, the outcomes assessed by the studies were limited due to fact that there was no report of different clinical manifestations associated to the disease, such as heart function, range of joint motion, and quality of life. The best evidence found in two systematic reviews refer to the same clinical trial published in 2006 (Harmatz et al. 2006), and another clinical trial (Harmatz et al. 2005) included only in one systematic review (El Dib and Pastores 2009). ...
Introduction
Mucopolysaccharidosis VI is a rare disease characterized by the arylsulfatase B enzyme deficiency, which is responsible for different clinical manifestations. The treatment consists of enzyme replacement therapy with intravenous administration of galsulfase.
Objective
Evaluate the effectiveness of the enzyme replacement therapy with galsulfase for the mucopolysaccharidosis VI treatment.
Method
Systematic review of observational studies. The databases of PubMed, Cochrane Library, Lilacs, and Journal of Inherited Metabolic Disease were reviewed. The selection of studies, data mining, and methodological quality assessment were independently conducted by two authors.
Results
Eighteen studies fulfilled the inclusion criteria. Two studies were cohorts, one was longitudinal study, one was cross-sectional, one was a case-control, eight were case series, and five were case reports. A total of 362 participants with mucopolysaccharidosis type VI were evaluated, and 14 different outcomes related to the treatment effect were identified. Seven outcomes showed positive results, characterized by the patient survival, quality of life, respiratory function, joint mobility, physical resistance, reduction of urinary glycosaminoglycans, and growth. The hearing function and the cognitive development were stable after the treatment. Other outcomes related to the cardiac function, visual acuity, sleep apnea, and the size of the liver and spleen presented inconclusive outcomes. Concerning safety, light adverse reactions of hypersensitivity were reported.
Conclusion
This review provided a broader panoramic view of the outcomes related to mucopolysaccharidosis type VI. Regardless of the inherent limitations of observational studies, the outcomes indicate that the enzyme replacement therapy has a positive effect on most of the outcomes associated to the disease.
... 11,12 In multiple clinical studies, including a randomized, double-blind, placebo-controlled phase 3 trial, Harmatz et al demonstrated that galsulfase administration to patients with MPS VI improved endurance when compared to placebo, as measured by the 12-minute walk test (12MWT), by the average number of steps climbed per minute in the 3-minute step climb test (3MSC), and by decreased urinary GAG excretion. [13][14][15][16] The physical improvements and the reduction in urinary GAG concentration were also shown to be sustained following long-term administration of galsulfase for up to 5 years. 17 A case report series by Lin et al 18,19 have also shown the long-term benefit of chronic galsulfase administered over 6.2 to 11.2 years to 9 Taiwanese patients with MPS VI ranging in age from 1.4 to 21.1 years at study initiation. ...
Mucopolysaccharidosis VI (MPS VI) is a progressive lysosomal storage disorder with multiorgan and multisystemic pathology. Currently, galsulfase enzyme replacement therapy (ERT) is the only approved treatment for MPS VI. A cross-sectional survey study of 121 patients with MPS VI conducted in 2001 to 2002 and a 10-year follow-up study of the same patients (resurvey study; ClinicalTrials.gov NCT01387854) found that those receiving galsulfase at any time showed physical improvements and a lower mortality rate (16.5%) versus treatment-naive patients (50%). After ∼15 years, galsulfase-treated patients (n = 104) continue to have a survival advantage over treatment-naive patients (n = 14), as demonstrated by a 24% versus 57% mortality rate. This survival advantage is further supported by data from the commercial use of galsulfase (2005-2016), which show a 5-year mortality rate for galsulfase-treated patients of 12.5%. Together, these findings suggest that galsulfase ERT can increase life expectancies for patients with MPS VI over a period of at least 15 years.
... Asociados a este beneficio, los valores de GAG urinarios disminuyeron en forma significativa y no hubo reacciones adversas serias. 18 Posteriormente otro estudio evaluó el crecimiento en 56 pacientes con MPS VI (5 a 29 años de edad) antes y durante 240 semanas de infusiones semanales con galsulfasa. Los puntos de eficacia terminal fueron los cambios en la talla, el peso y el estadio de Tanner. ...
... All but five patients received galsulfase (Naglazyme®, BioMarin Pharmaceutical Inc., Novato, CA) infusions at 1 mg/kg weekly according to the prescribing information [13] and recommended standard of care [14]. Of the remaining five patients, three received 0.2 mg/kg during the Phase 1/2 clinical trial (NCT00048620) [15] and two received 2 mg/kg in a Phase 4 study (NCT00299000) [7,16]. All five patients subsequently received the 1 mg/kg/week dose. ...
Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200μg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0–3, >3–6, >6–9, >9–12, and >12–15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200μg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.
... Other reported adverse events following galsulfase include headache, pyrexia, limb, chest and ear pain, visual abnormalities, anxiety, dyspepsia, upper respiratory infection,s and cough [138,139] (Table 2). In their extended examination of galsulfase therapy for MPS VI in phase I, II, III, and longterm follow-up studies, Harmatz and colleagues [140][141][142][143] observed an incidence of infusion reactions of 20-75 %. Serious drug-related adverse events were uncommon, with a total of only 1.8 % of patients experiencing such reactions in the published studies; three of the more serious were asthma, apnea, and urticaria. ...
Research and drug developments fostered under orphan drug product development programs have greatly assisted the introduction of efficient and safe enzyme-based therapies for a range of rare disorders. The introduction and regulatory approval of 20 different recombinant enzymes has enabled, often for the first time, effective enzyme-replacement therapy for some lysosomal storage disorders, including Gaucher (imiglucerase, taliglucerase, and velaglucerase), Fabry (agalsidase alfa and beta), and Pompe (alglucosidase alfa) diseases and mucopolysaccharidoses I (laronidase), II (idursulfase), IVA (elosulfase), and VI (galsulfase). Approved recombinant enzymes are also now used as therapy for myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dornase alfa), chronic gout (pegloticase), tumor lysis syndrome (rasburicase), leukemia (L -asparaginase), some collagen-based disorders such as Dupuytren's contracture (collagenase), severe combined immunodeficiency disease (pegademase bovine), detoxification of methotrexate (glucarpidase), and vitreomacular adhesion (ocriplasmin). The development of these efficacious and safe enzyme-based therapies has occurred hand in hand with some remarkable advances in the preparation of the often specifically designed recombinant enzymes; the manufacturing expertise necessary for commercial production; our understanding of underlying mechanisms operative in the different diseases; and the mechanisms of action of the relevant recombinant enzymes. Together with information on these mechanisms, safety findings recorded so far on the various adverse events and problems of immunogenicity of the recombinant enzymes used for therapy are presented.
... Asociados a este beneficio, los valores de GAG urinarios disminuyeron en forma significativa y no hubo reacciones adversas serias. 18 Posteriormente otro estudio evaluó el crecimiento en 56 pacientes con MPS VI (5 a 29 años de edad) antes y durante 240 semanas de infusiones semanales con galsulfasa. Los puntos de eficacia terminal fueron los cambios en la talla, el peso y el estadio de Tanner. ...
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease associated with a deficiency or absence of arylsulfatase B leading to the abnormal accumulation of dermatan sulfate. MPS VI shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic spectrum includes skeletal displasia, coarse facies, cardiomyopathy, pulmonary complications and spinal compression. Diagnosis generally requires measurement ofurinary glycosaminoglycans and arylsulfatase B enzyme activity in dried blood spot, leukocytes or cultured fibroblasts. Enzyme replacement therapy (ERT) with galsulfase is now widely available providing improvement in skeletal performance and stabilization in pulmonary and cardiac functioning. Spinal involvement does not respond to ERT when is present, surgical decompression should be indicated early. Prognosis is variable depending on the age of onset and age at initiation of ERT.
... International management guidelines for MPS VI recommend galsulfase ERT as the first-line therapy for treating MPS VI patients . Three clinical trials, including a randomized double-blind placebo-controlled Phase 3 trial, showed improved endurance based on increased 12-minute walk test (12MWT) and 3-minute stairclimb (3MSC) measurements, and decreased urinary GAGs, demonstrating efficacy of galsulfase in the MPS VI patients [Harmatz et al., 2006;Harmatz et al., 2005a;Harmatz et al., 2005b;Harmatz et al., 2004]. An analysis of pooled data from the clinical trial program showed improvement in pulmonary function tests and growth velocity in patients (n=56, mean age approximately 12 years, range 5 to 29 years) who received ERT for up to 240 weeks Harmatz et al., 2010]. ...
Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4–7-year-old baseline age group and by 16.8 cm in the 8–12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10–0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival. © 2014 Wiley Periodicals, Inc.
... In contrast, as previously reported in cats and humans (Crawley et al., 1996;Harmatz et al., 2005b), rhARSB was rapidly cleared from the circulation after enzyme infusion and dropped to undetectable levels 5 hr after the infusion FIG. 1. Serum ARSB levels in MPS VI mice treated with either AAV-mediated gene therapy (a) or enzyme replacement therapy (b). (a) MPS VI mice were injected with 2 · 10 12 gc/kg of AAV2/8.TBG.hARSB at postnatal day 30 (p30). ...
Abstract Enzyme replacement therapy (ERT) has become the standard of care for several lysosomal storage disorders (LSDs). Despite ERT's undisputed efficacy, the requirement for multiple and costly administrations as well as ERT's limited improvement of some LSD manifestations prompts the search for better therapies. Using a mouse model of mucopolysaccharidosis VI, we compared the efficacy of a single intravascular administration of an adeno-associated viral vector targeting liver to weekly infusions of human recombinant enzyme at the same doses used in mucopolysaccharidosis VI patients. While gene therapy results in increased and stable levels of circulating enzyme up to 1 year after vector administration, ERT has typical peak-and-drop serum kinetics. Both therapies similarly reduced glycosaminoglycan levels in urine and tissues including heart valves and myocardium, with gene therapy improving skeletal skull abnormalities slightly better, although not significantly, than ERT. Both therapies seem to similarly improve animal motor performance, with gene therapy possibly associated with less animal distress. Thus, a single vector administration that converts liver into a factory organ for systemic secretion of therapeutic proteins is at least as effective as ERT in a mouse model of LSD, potentially eliminating problems with compliance and costs. Only testing in humans will prove whether this holds true in a clinical setting.
... El primer estudio clínico controlado aleatorizado, doble ciego y multicéntrico, incluyó a 39 pacientes, donde los que recibieron galsulfasa luego de 24 semanas presentaron una mejoría significativa en el test 6MWK y el test 3MSC. Asociado a este beneficio, los valores de GAG urinarios disminuyeron en forma significativa y no hubo reacciones adversas serias 15 . ...
Mucopolysaccharidosis vi is a lysosomal storage disease due a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. The disease shows a wide spectrum of symptoms from slowly to rapidly progressing forms. Neurological aspects are spinal compression, hydrocephalus and nerve entrapment. Diagnosis requires measurement of urinary glycosaminoglycans and arylsulfatase B activity in dried blood spot, leukocytes or cultured fibroblasts. Enzyme replacement therapy (ERT) showed improvement in skeletal, pulmonary and cardiac functioning. Spinal involvement does not respond to ERT when is present, surgical decompression should be indicated early.
... The intravenous administration of recombinant human enzyme replacement therapy has revolutionized the treatment of several lysosomal storage diseases. Recombinant enzyme is currently in clinical use for Gaucher disease; Fabry disease; mucopolysaccharidosis I, II, and VI; and Pompe disease (Kakkis et al. 2001;Wraith et al. 2004;Muenzer et al. 2006;Harmatz et al. 2005; Barton et al. 1991;Eng et al. 2001;Schiffmann et al. 2000). Enzyme replacement therapy improves many aspects of these disorders and in many cases has enabled patients to lead more normal lives. ...
The immune response to exogenous protein has been shown to reduce therapeutic efficacy in animal models of enzyme replacement therapy. A previously published study demonstrated an immunosuppressive regimen which successfully induced immune tolerance to α-L-iduronidase in canines with mucopolysaccharidosis I. The two key requirements for success were high-affinity receptor-mediated enzyme uptake, conferred by mannose 6-phosphate conjugation, and immunosuppression with low-dose antigen exposure. In this study, we attempted to induce immune tolerance to phenylalanine ammonia-lyase by producing a recombinant mannose 6-phosphate conjugated form and administering it to normal dogs according to the previously published tolerance induction regimen. We found that the recombinant conjugated enzyme was stable, could bind to the mannose 6-phosphate receptor with high affinity, and its uptake into fibroblast cells was mediated by this receptor. However, at the end of a tolerance induction period, all dogs demonstrated an antigen-specific immune response when challenged with increasing doses of unconjugated phenylalanine ammonia-lyase. The average time to seroconvert was not significantly different among three separate groups of test animals (n = 3 per group) and was not significantly different from one group of control animals (n = 3). None of the nine test group animals developed immune tolerance to the enzyme using this method. This suggests that high-affinity cellular uptake mediated by the mannose 6-phosphate receptor combined with a previously studied tolerizing regimen is not sufficient to induce immune tolerance to an exogenous protein and that other factors affecting antigen distribution, uptake, and presentation are likely to be important.
... First, despite reduction of visceromegaly and improvement of endurance, ERT failed to ameliorate cardiac and visual function and bone abnormalities, likely because of the limited biodistribution of recombinant human ARSB (rhARSB) (Harmatz et al., 2004;Harmatz et al., 2005a;Harmatz et al., 2006;Harmatz et al., 2008). Second, the requirement of weekly intravenous infusions as a result of the rhARSB short half-life (Crawley et al., 1996;Harmatz et al., 2005b) carries the risk of anaphylactic reactions and results in limited compliance to the therapy. Third, ERT has extremely high costs preventing access to therapy for patients in less-developed countries. ...
Liver gene transfer with adeno-associated viral (AAV) 2/8 vectors is being considered for therapy of systemic diseases like mucopolysaccharidosis VI (MPS VI), a lysosomal storage disease due to deficiency of arylsulfatase B (ARSB). We have previously reported that liver gene transfer with AAV2/8 results in sustained yet variable expression of ARSB. We hypothesized that the variability we observed could be due to pre-existing immunity to wild-type AAV8. To test this, we compared the levels of AAV2/8-mediated transduction in MPS VI cats with and without preexisting immunity to AAV8. In addition, since levels of lysosomal enzymes as low as 5% of normal are expected to be therapeutic, we evaluated the impact of pre-existing immunity on MPS VI phenotypic rescue. AAV2/8 administration to MPS VI cats without pre-existing neutralizing antibodies to AAV8 resulted in consistent and dose-dependent expression of ARSB, urinary glycosaminoglycan (GAG) reduction, and femur length amelioration. Conversely, animals with pre-existing immunity to AAV8 showed low levels of ARSB expression and limited phenotypic improvement. Our data support the use of AAV2/8-mediated gene transfer for MPS VI and other systemic diseases, and highlight that pre-existing immunity to AAV8 should be considered in determining subject eligibility for therapy.
... Most MPS patients receiving ERT develop antibodies, as patients with these disorders have absent or very low residual enzyme activity and thus the normal active protein [33] Pulmonary function [30] v54 www.rheumatology.oxfordjournals.org severely affected patients with MPS I, antibody titre is inversely related to the reduction in urinary GAG level achieved. ...
Better understanding of disease pathophysiology, improved supportive care and availability of disease-specific treatments for some of the mucopolysaccharidosis (MPS) disorders have greatly improved the outlook for patients with MPS disorders. Optimal management of these multisystemic disorders involves a multidisciplinary team and regular, comprehensive follow-up. Enzyme replacement therapy (ERT) is now available for MPS I (Hurler, Hurler-Scheie and Scheie syndromes) (laronidase), MPS II (Hunter syndrome) (idursulfase) and MPS VI Maroteaux-Lamy (galsulfase), and is in development for MPS IV (Morquio syndrome) and MPS VII (Sly syndrome). Benefits of ERT can include improved walking ability, improved respiration and enhanced quality of life. Haematopoietic stem cell transplantation (HSCT) can preserve cognition and prolong survival in very young children with the most severe form of MPS I, and is under investigation for several other MPS disorders. Better tissue matching techniques, improved graft-vs-host prophylaxis and more targeted conditioning regimens have improved morbidity and mortality associated with HSCT.
... del of MPS VI (cats) showed that administration of galsulfase produced a significant improvement in some signs of the disease (Bielicki et al., 1999; Turner et al., 1999; Kakkis, 2002; Auclair et al., 2003). They also showed a decrease in GAG storage in organs, an increase in joint mobility, and prevention or slowed progression of skeletal disease. Harmatz et al. (2005b) was performed in six patients, using two different doses of the drug, 1 mg/kg and 0.2 mg/kg, given in weekly infusions during 48 weeks. Summary of the main study findings: (a) The drug was well tolerated; (b) There was a reduction in GAG excretion via the urine. Phase II -The study, performed in 10 patients, used the 1 mg/kg dose establ ...
Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.
... Six subjects with confirmed MPS VI were recruited and informed consent obtained as part of the Phase 1/2 study of rhASB [12]. Standing height was measured and volumetric bone mineral density (vBMD) was determined by quantitative computed tomography (QCT) in coordination with liver volume assessment at 4 time points: baseline then at 24, 96 and 144 weeks after initiation of rhASB therapy. ...
Enzyme replacement therapy has been successful in alleviating morbidity and improving endurance in Mucopolysaccharidosis (MPS) type I, II, and VI, however little attention has been paid to the effects on bone mineralization. Brief case reports in MPS type III and IV suggest that bone mineral density (BMD) is diminished, but did not account for patient size. In this report, BMD was evaluated by quantitative computed tomography and by dual-energy x-ray absorptiometry (DXA) in separate studies involving 10 patients with MPS type VI (7 Female; 7.0 to 21.0 y) and 4 male patients with MPS II (8.1 to 35.5 y). Vitamin D intake met the current RDA (200 IU) for most, though 25-OH vitamin D was insufficient (< 30 ng/mL) in 87.5% of patients tested. Ht Z-score was low -5.8 +/- 3.6, with height deficits greatest in MPS VI. Spine and whole body BMD Z-scores by DXA were considered normal for chronological age in all MPS II, and after correction for Ht Z-score, in all but one subject with MPS VI. These results suggest that vitamin D insufficiency is quite common in MPS. BMD by DXA is within normal range for most, particularly after correction for short stature. A review of bone health assessment is provided as well as a discussion of these results.
... Extensive preclinical studies were completed in a feline model of MPS VI [80] 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 1/2, Phase 2 and Phase 3 human clinical trials99100101102 . Significant improvements in 12-minute-walk test, nearly significant improvement in 3-minute stair climb and significant reduction in uGAG levels were demonstrated in the 24-week, randomized, double-blind Phase 3 trial [102]. ...
Abstract Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally
... Enzyme replacement therapy (ERT) is used weekly or every other week to treat patients with the lysosomal storage disesases Gaucher syndrome, Fabry disease, Pompe disease, and mucopolysaccharidoses (MPS) I, II, and VI (Barton et al 1991;Kakkis et al 2001;Eng et al 2001;Harmatz et al 2005;Kishnani et al 2006;Muenzer J et al 2006). In MPS I patients, weekly infusions of 0.58 mg/kg intravenous recombinant human α-L-iduronidase (laronidase, rhIDU, EC 3.1.2.76) improve hepatosplenomegaly, pulmonary function, ambulation, joint mobility, and cardiac functional class (Kakkis et al 2001). ...
Intravenous enzyme replacement therapy with recombinant human alpha-L: -iduronidase (rhIDU) is used weekly to treat mucopolysaccharidosis (MPS) I. We tested continuous administration of rhIDU at two dosing levels (0.58 mg/kg per week and 2 mg/kg per week) in MPS I dogs, and compared the efficacy of continuous infusion with the clinically used 0.58 mg/kg weekly three-hour infusion. Peak plasma concentrations of rhIDU were much higher in weekly-treated dogs (mean 256 units/ml) than steady-state concentrations in dogs treated with continuous infusion (mean 1.97 units/ml at 0.58 mg/kg per week; 8.44 units/ml at 2 mg/kg per week). Dogs receiving continuous IV rhIDU, even at a higher (2 mg/kg per week) dose, had consistently lower iduronidase levels in tissues than dogs receiving a weekly (0.58 mg/kg per week) dose. GAG storage was also less improved by continuous intravenous infusion. Adverse events were similar in all dosing groups. We found that continuous administration of 2 mg/kg per week rhIDU to MPS I dogs was insufficient to achieve GAG storage reduction comparable to 0.58 mg/kg weekly dosing.
Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In this review, we discuss specific examples of how variations in glycan structure and glycoengineering impacts the stability, safety, and clinical efficacy of protein-based drugs that are already in the market as well as those that are still in preclinical development. We also highlight the impact of glycosylation on next generation biologics such as T cell-based cancer therapy and gene therapy.
Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In this review, we discuss specific examples of how variations in glycan structure and glycoengineering impacts the stability, safety, and clinical efficacy of protein-based drugs that are already in the market as well as those that are still in preclinical development. We also highlight the impact of glycosylation on next generation biologics such as T cell-based cancer therapy and gene therapy.
Background:
Mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome is a rare genetic disorder caused by the deficiency of arylsulphatase B. The resultant accumulation of dermatan sulphate causes lysosomal damage. The clinical symptoms are related to skeletal dysplasia (i.e. short stature and degenerative joint disease). Other manifestations include cardiac disease, impaired pulmonary function, ophthalmological complications, hepatosplenomegaly, sinusitis, otitis, hearing loss and sleep apnea. Intellectual impairment is generally absent. Clinical manifestation is typically by two or three years of age; however, slowly progressive cases may not present until adulthood. Enzyme replacement therapy (ERT) with galsulfase is considered a new approach for treating MPS VI.
Objectives:
To evaluate the effectiveness and safety of treating MPS VI by ERT with galsulfase compared to other interventions, placebo or no intervention.
Search methods:
Eletronic searches were performed on the Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register. Date of the latest search: 09 June 2021. Further searches of the following databases were also performed: CENTRAL, MEDLINE, LILACS, the Journal of Inherited Metabolic Disease, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Date of the latest search: 20 August 2021.
Selection criteria:
Randomized and quasi-randomized controlled clinical studies of ERT with galsulfase compared to other interventions or placebo.
Data collection and analysis:
Two authors independently screened the studies, assessed the risk of bias, extracted data and assessed the certainty of the the evidence using the GRADE criteria.
Main results:
One study was included involving 39 participants who received either ERT with galsulfase (recombinant human arylsulphatase B) or placebo. This small study was considered overall to have an unclear risk of bias in relation to the design and implementation of the study, since the authors did not report how both the allocation generation and concealment were performed. Given the very low certainty of the evidence, we are uncertain whether at 24 weeks there was a difference between groups in relation to the 12-minute walk test, mean difference (MD) of 92.00 meters (95% confidence interval (CI) 11.00 to 172.00), or the three-minute stair climb, MD 5.70 (95% CI -0.10 to 11.50). In relation to respiratory tests, we are uncertain whether galsulfase makes any difference as compared to placebo in forced vital capacity in litres (FVC (L) (absolute change in baseline), given the very low certainty of the evidence. Cardiac function was not reported in the included study. We found that galsulfase, as compared to placebo, may decrease urinary glycosaminoglycan levels at 24 weeks, MD -227.00 (95% CI -264.00 to -190.00) (low-certainty evidence). We are uncertain whether there are differences between the galsulfase and placebo groups in relation to adverse events (very low-certainty evidence). In general, the dose of galsulfase was well tolerated and there were no differences between groups. These events include drug-related adverse events, serious and severe adverse events, those during infusion, drug-related adverse events during infusion, and deaths. More infusion-related reactions were observed in the galsulfase group and were managed with interruption or slowing of infusion rate or administration of antihistamines or corticosteroids drugs. No deaths occurred during the study. AUTHORS' CONCLUSIONS: The results of this review are based only on one small study (a 24-week randomised phase of the study and prior to the open-label extension). We are uncertain whether galsulfase is more effective than placebo, for treating people with MPS VI, in relation to the 12-minute walk test or the three-minute stair climb, as the certainty of the evidence has been assessed as very low. We found that galsulfase may reduce urinary glycosaminoglycans levels. We are also uncertain whether there are any differences between treatment groups in relation to cardiac or pulmonary functions, liver or spleen volume, overnight apnea-hypopnea, height and weight, quality of life and adverse effects. Further studies are needed to obtain more information on the long-term effectiveness and safety of ERT with galsulfase.
Introduction
Mucopolysaccharidosis VI is a rare disease characterized by the arylsulfatase B enzyme deficiency, which is responsible for different clinical manifestations. The treatment consists of enzyme replacement therapy with intravenous administration of galsulfase.
Objective
Evaluate the effectiveness of the enzyme replacement therapy with galsulfase for the mucopolysaccharidosis VI treatment.
Method
Systematic review of observational studies. The databases of PubMed, Cochrane Library, Lilacs, and Journal of Inherited Metabolic Disease were reviewed. The selection of studies, data mining, and methodological quality assessment were independently conducted by two authors.
Results
Eighteen studies fulfilled the inclusion criteria. Two studies were cohorts, one was longitudinal study, one was cross‐sectional, one was a case–control, eight were case series, and five were case reports. A total of 362 participants with mucopolysaccharidosis type VI were evaluated, and 14 different outcomes related to the treatment effect were identified. Seven outcomes showed positive results, characterized by the patient survival, quality of life, respiratory function, joint mobility, physical resistance, reduction of urinary glycosaminoglycans, and growth. The hearing function and the cognitive development were stable after the treatment. Other outcomes related to the cardiac function, visual acuity, sleep apnea, and the size of the liver and spleen presented inconclusive outcomes. Concerning safety, light adverse reactions of hypersensitivity were reported.
Conclusion
This review provided a broader panoramic view of the outcomes related to mucopolysaccharidosis type VI. Regardless of the inherent limitations of observational studies, the outcomes indicate that the enzyme replacement therapy has a positive effect on most of the outcomes associated to the disease.
Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis. Here we evaluated whether the combination of low doses of AAV2/8 with a less frequent (monthly) than canonical (weekly) ERT schedule may be as effective as the single treatments at high doses or frequent regimen. A greater reduction of both urinary glycosaminoglycans, considered a sensitive biomarker of therapeutic efficacy, and storage in the myocardium and heart valves was observed in mice receiving the combined than the single therapies. Importantly, these levels of correction were similar to those we obtained in a previous study following either high doses of AAV2/8 or weekly ERT. Our data show that low-dose gene therapy can be used as a means to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.
Lysosomal storage disorders are inherited metabolic disorders resulting from progressive accumulation of non-recycled compounds that build-up in the lysosomes before expanding to most of body tissues and organs. Impaired enzyme activity, molecular trafficking and transport of these proteins resulting from genetic mutations constitute the main pathogenic mechanisms. Clinical manifestations include storage signs and symptoms such as enlarged liver and spleen, coarse features, skeletal deformities and many of them are associated with a neurodegenerative course. Clinical suspicion can be supported by detection of accumulation of abnormal compounds such as mucopolysaccharides, oligosaccharides, sialic acid and free cholesterol in body fluids and tissues, confirmed by enzymatic assays and molecular testing allowing also prenatal diagnosis and genetic counseling. Management of lysosomal storage disorders can be symptomatic but also specific for some of them with two main treatment modalities: hematopoietic stem cell transplantation and enzyme replacement therapy. Despite recent progress in the field, access of these therapies to key organs such as the brain and bone remain challenging and may be addressed in the near future by original or complementary approaches including molecular chaperones, substrate inhibitors and gene therapy. From this perspective, medical awareness and early detection constitute the cornerstones for early intervention and hope for a better outcome.
According to IARC a figures "rare and less common" cancers comprise more than a third of all cancer diagnoses as a group. However, advances in molecular biology have resulted in novel ways to classify cancers based upon genetic alterations and not just anatomical location, and this revised classification is at the heart of any move toward more personalised healthcare. It is now increasingly accepted that cancer should be thought of as many hundreds of more rare subtypes, each of which will have specific therapeutic options. We have selected colorectal carcinoma to illustrate the concept that each cancer is "rare", and demonstrate why this is important for delivering on the concept of Predictive, Preventive and Personalised Medicine (PPPM) for cancer in terms of prediction of who will get the disease, how it will behave and how to prevent it.
Background
The treatment of inborn errors of metabolism (IEM) has seen significant advances over the last decade. Many medicines have been developed and the survival rates of some patients with IEM have improved. Dosages of drugs used for the treatment of various IEM can be obtained from a range of sources but tend to vary among these sources. Moreover, the published dosages are not usually supported by the level of existing evidence, and they are commonly based on personal experience.
Methods
A literature search was conducted to identify key material published in English in relation to the dosages of medicines used for specific IEM. Textbooks, peer reviewed articles, papers and other journal items were identified. The PubMed and Embase databases were searched for material published since 1947 and 1974, respectively. The medications found and their respective dosages were graded according to their level of evidence, using the grading system of the Oxford Centre for Evidence-Based Medicine.
Results
83 medicines used in various IEM were identified. The dosages of 17 medications (21%) had grade 1 level of evidence, 61 (74%) had grade 4, two medications were in level 2 and 3 respectively, and three had grade 5.
Conclusions
To the best of our knowledge, this is the first review to address this matter and the authors hope that it will serve as a quickly accessible reference for medications used in this important clinical field.
Spinal cord compression (SCC) is a known complication of mucopolysaccharidosis type VI (MPS VI) secondary to atlantoaxial subluxation, craniovertebral stenosis, posterior longitudinal ligament hypertrophy, or dural thickening. SCC is expected to occur in the natural history of the disease, regardless of enzyme replacement therapy (ERT), as intravenous enzyme does not cross the blood-brain barrier. We describe six MPS VI children with SCC, all diagnosed before 7years of age. Within this group, four of the children were diagnosed with SCC after the introduction of ERT. We hypothesize that these patients may illustrate the previously undetected risk of increased joint mobility caused by ERT which may have contributed to increased cervical instability by loosening the neck joint, thus leading to or unmasking SCC. We reinforce the need for close follow-up of SCC, periodic neurological assessment, spine imaging, and neurophysiology in all MPS VI patients before and during ERT. Neurophysiological abnormalities may precede changes in MRI images (as shown in patients 4 and 5 from this sample) and should, therefore, be accessed in MPS VI patient evaluations, allowing for timely intervention and better prognosis. We recognize the limitations of these data due to the small sample size and recommend further investigation into this patient population.
To develop educational guidelines for the diagnostic confirmation and management of individuals identified by newborn screening, family-based testing after proband identification, or carrier testing in at-risk populations, and subsequent prenatal or postnatal testing of those who are presymptomatic for a lysosomal storage disease.
Review of English language literature and discussions in a consensus development panel comprised an international group of experts in the clinical and laboratory diagnosis, treatment and management, newborn screening, and genetic aspects of lysosomal storage diseases.
Although clinical trial and longitudinal data were used when available, the evidence in the literature is limited and consequently the recommendations must be considered as expert opinion. Guidelines were developed for Fabry, Gaucher, and Niemann-Pick A/B diseases, glycogen storage type II (Pompe disease), globoid cell leukodystrophy (Krabbe disease), metachromatic leukodystrophy, and mucopolysaccharidoses types I, II, and VI.
These guidelines serve as an educational resource for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have a lysosomal storage disease; they also help to define a research agenda for longitudinal studies such as the American College of Medical Genetics/National Institutes of Health Newborn Screening Translational Research Network.
Mucopolysaccharidosis VI (MPS VI) is an inheritable, clinically heterogeneous lysosomal storage disorder that develops due to a deficiency in the arylsulfatase B (ASB) enzyme. This deficiency impairs the stepwise degradation of glycosaminoglycans (GAGs) resulting in the accumulation of partially degraded GAGs in tissues and organs throughout the body. A relatively novel therapy for MPS VI is enzyme replacement therapy (ERT) with human recombinant ASB (galsulfase). This manuscript gives an overview of all clinical trials that have evaluated the efficacy and safety of ERT with galsulfase in patients with MPS VI to date and discusses the outcome of these trials.
Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80's treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90's, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.
Mucopolysaccharidosis (MPS) IIIB is an inherited lysosomal storage disorder caused by deficiency of alpha-N-acetylglucosaminidase (NAGLU). The disease is characterized by mild somatic features and severe neurological involvement, with high mortality rates. Although some therapeutic approaches have been applied to the murine model of the disease, no effective therapy is available. Moreover, assessing therapeutic efficacy is challenged by the lack of markers to for progression and severity. In this study, we examined the effect of brain-directed lentiviral (LV) gene therapy on serum levels of macrophage inflammatory protein 1 alpha (MIP-1alpha) and brain-derived neurotrophic factor (BDNF) proteins in the murine model of MPS IIIB to identify novel serum biomarkers. The cytokine MIP-1alpha was elevated in MPS IIIB mouse serum, and following gene therapy, it was reduced to normal levels. For neurotrophin BDNF, the difference in serum levels between MPS IIIB and normal mice was not statistically significant; after LV gene therapy, an increase in protein was found in treated mice, although the values were not statistically significant. Our studies suggest MIP-1alpha as the first serum biomarker that could be used to monitor disease progression and treatment for MPS IIIB disease.
Mucopolysaccharidoses (MPSs) are lysosomal storage disorders characterized by progressive accumulation of glycosaminoglycans (GAGs) in various tissues. Enzyme replacement therapy (ERT) for several MPSs is available to date. However, the efficacy of ERT is limited, in particular in compartments such as bone, cartilage, the brain, and the eyes. We selected a rodent model of an MPS, with no central nervous system storage, to study the impact, on systemic features of the disease, of various stable levels of exogenous enzymes produced by adeno-associated viral vector (AAV)-mediated liver gene transfer. Low levels (6% of normal) of circulating enzyme were enough to reduce storage and inflammation in the visceral organs and to ameliorate skull abnormalities; intermediate levels (11% of normal) were required to reduce urinary GAG excretion; and high levels (>or=50% of normal) rescued abnormalities of the long bones and motor activity. These data will be instrumental to design appropriate clinical protocols based on either enzyme or gene replacement therapy for MPS and to predict their impact on the pathological features of MPS.
Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) is an autosomal recessive lysosomal storage disorder, characterized primarily by skeletal dysplasia and joint contracture. It is caused by a deficiency of N-acetylgalactosamine-4-sulfatase (arylsulfatase B), for which a recombinant formulation (galsulfase) is available as replacement therapy.
To evaluate the effectiveness and safety of galsulfase compared to placebo or no interventions, for treating MPS VI. We also considered studies evaluating different doses of galsulfase.
A systematic review of the literature was conducted. A computerized electronic search in MEDLINE, EMBASE, CENTRAL, SciELO, and LILACS was carried on to identify any randomized trials that met our inclusion criteria.
Two studies were included in the review. Because the number of studies was small, our analysis probably did not find any statistically significant difference. Long-term follow-up will be required to ascertain full clinical benefit, on both event-free survival and quality of life measures.
There is some evidence to support the use of galsulfase in the treatment of MPS VI; however due to the very low quantity of included studies we could not analyze it in an appropriate way. This review highlights the need for continued research into the use of enzyme replacement therapy for MPS VI.
Surface enhanced laser desorption/ionisation time of flight (SELDI-TOF) mass spectrometry has been used to search for new protein biomarkers in the plasma of patients with mucopolysacharidoses (MPS). Differences in the levels of some plasma proteins, particularly the apolipoprotein ApoCI, were observed between MPS patients and normal controls, using the different chromatographic surfaces (ProteinChips). ApoCI was identified by both its mass and by immunological techniques. In plasma, it exists in two forms, ApoCI and a truncated form which lacks two N-terminal amino acids, ApoCI'. In controls, the ratio of ApoCI':ApoCI observed using the cation-exchange surface (CM10) was approximately 1:2 whereas in most MPS patients it varied from 1:1 to 1:0.8. The ratio of ApoCI':ApoCI in plasma is determined by the activity of dipeptidyl peptidase IV, DPP-IV (also known as the leucocyte antigen CD26), which was found to be elevated up to 3-fold in MPS patients. The DPP-IV activity decreased in MPS I patients undergoing enzyme replacement therapy, indicating that it could be a useful biomarker for monitoring the efficacy of treatment in MPS disease. As DPP-IV has an important regulatory role in metabolism, it is possible that its elevation could cause some of the secondary pathology in MPS, and inhibition of DPP-IV might have a role in MPS therapy.
This direct method for quantifying excessive urinary glycosaminoglycan excretion exploits the specific binding of 1,9-dimethylmethylene blue (DMB). The procedure obviates cumbersome and labor-intensive procedures for separating glycosaminoglycans from other constituents of urine. Pediatric pharmaceutical formulations (except heparin), in concentrations expected in urine, do not interfere with spectrophotometry, nor does protein. Results can be expressed in terms of urinary creatinine; thus the test is applicable to very small urine specimens (0.1 mL), such as those obtainable from neonates. In a pilot study, results of the direct DMB test for 48 urine specimens agreed with the clinical diagnosis, and quantitative measurements correlated moderately (r = 0.76) with results of a commonly used procedure (carbazole-borate reactivity after precipitation with cetylpyridinium chloride). The present method was also used to assess metabolic correction in a patient with Hurler's syndrome after treatment by bone-marrow transplantation. This quantitative method surmounts the major technical problems of developing mass screening programs for infants, thus offering the potential for earlier diagnosis and treatment of mucopolysaccharidosis diseases.
We report studies that suggest enzyme replacement therapy will result in a significant reduction in disease progression and tissue pathology in patients with Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI, MPS VI). A feline model for MPS VI was used to evaluate tissue distribution and clinical efficacy of three forms of recombinant human N-acetylgalactosamine-4-sulfatase (rh4S, EC 3.1.6.1). Intravenously administered rh4S was rapidly cleared from circulation. The majority of rh4S was distributed to liver, but was also detected in most other tissues. Tissue half-life was approximately 2-4 d. Three MPS VI cats given regular intravenous infusions of rh4S for up to 20 mo showed variable reduction of storage vacuoles in Kupffer cells and connective tissues, however cartilage chondrocytes remained vacuolated. Vertebral bone mineral volume was improved in two MPS VI cats in which therapy was initiated before skeletal maturity, and increased bone volume appeared to correlate with earlier age of onset of therapy. One cat showed greater mobility in response to therapy.
In a feline model of mucopolysaccharidosis type VI (MPS VI), recombinant feline N-acetylgalactosamine-4-sulfatase (rf4S) administered at a dose of 1 mg/kg of body weight, altered the clinical course of the disease in two affected cats treated from birth. After 170 days of therapy, both cats were physically indistinguishable from normal cats with the exception of mild corneal clouding. Feline N-acetylgalactosamine-4-sulfatase was effective in reducing urinary glycosaminoglycan levels and lysosomal storage in all cell types examined except for corneal keratocytes and cartilage chondrocytes. In addition, skeletal pathology was nearly normalized as assessed by radiographic evidence and bone morphometric analysis. Comparison of results with a previous study in which recombinant human 4S (rh4S) was used at an equivalent dose and one 5 times higher indicated that rf4S had a more pronounced effect on reducing pathology than the same dose of rh4S, and in some instances such as bone pathology and lysosomal storage in aorta smooth muscle cells, it was as good as, or better than, the higher dose of rh4S. We conclude that in the feline MPS VI model the use of native or same species enzyme for enzyme replacement therapy has significant benefits.
This direct method for quantifying excessive urinary glycosaminoglycan excretion exploits the specific binding of 1,9-dimethylmethylene blue (DMB). The procedure obviates cumbersome and labor-intensive procedures for separating glycosaminoglycans from other constituents of urine. Pediatric pharmaceutical formulations (except heparin), in concentrations expected in urine, do not interfere with spectrophotometry, nor does protein. Results can be expressed in terms of urinary creatinine; thus the test is applicable to very small urine specimens (0.1 mL), such as those obtainable from neonates. In a pilot study, results of the direct DMB test for 48 urine specimens agreed with the clinical diagnosis, and quantitative measurements correlated moderately (r = 0.76) with results of a commonly used procedure (carbazole-borate reactivity after precipitation with cetylpyridinium chloride). The present method was also used to assess metabolic correction in a patient with Hurler's syndrome after treatment by bone-marrow transplantation. This quantitative method surmounts the major technical problems of developing mass screening programs for infants, thus offering the potential for earlier diagnosis and treatment of mucopolysaccharidosis diseases.
Maroteaux-Lamy syndrome is a mucopolysaccharidosis due to an enzymatic deficiency of arylsulfatase B (N-acetylgalactosamine-4-sulfatase) (ASB; EC 3.1.6.1) in the leukocytes, fibroblasts and tissues. This storage disease is inherited as an autosomal recessive. The clinical description includes presentation with hepatosplenomegaly, dysostosis multiplex with later development of pulmonary and cardiac insufficiency. Bone marrow transplantation has successfully corrected the enzymatic defect in 6 patients. The gene for the arylsulfatase B has been characterized and cloned. A vector has been constructed into which the normal gene has been inserted. The normal gene with the vector has been introduced into fibroblasts from Maroteaux-Lamy patients and normal, and even greater than normal, amounts of arylsulfatase B have been produced. Previously, the experimental feline model of arylsulfatase B has been successfully treated by allogeneic bone marrow transplantation. The material presented in this article includes a review of the above data and a consideration of therapeutic approaches for the future.
A 13-year-old girl with the severe form of the Maroteaux-Lamy syndrome (mucopolysaccharidosis Type VI, arylsulfatase B deficiency) has had successful reconstitution with bone marrow from her HLA-MLC-matched sister who had normal arylsulfatase B activity. Full engraftment has been present for 24 months. The following biochemical and clinical changes have occurred: arylsulfatase B activity in peripheral lymphocytes and granulocytes increased to normal levels, and the activity in serial liver-biopsy specimens increased from about 3 per cent of the mean normal level 43 days after transplantation to about 16 per cent at 600 days. Urinary excretion of acid mucopolysaccharide decreased. Ultrastructural evidence of accumulated dermatan sulfate was no longer detectable in bone-marrow cells; in peripheral-blood lymphocytes, granulocytes, or platelets; or in Ito cells of liver. Twenty-four months after engraftment, hepatosplenomegaly was substantially decreased and cardiopulmonary function was normal. Visual acuity and joint mobility were also improved. The patient returned to school and continued to perform well in academic studies. Thus, bone-marrow transplantation provided a source of enzymatically normal cells, which have altered the metabolic and clinical course of the disease.
Patients with lysosomal storage disorders have visceral, skeletal, and neurological abnormalities and a limited life expectancy. Bone marrow transplantation has been used to correct the metabolic defects and leads to metabolic improvements in most patients. However, the long-term effect of such therapy is uncertain. We analysed the data from 63 patients transplanted for lysosomal storage diseases. The transplant-related mortality was 10% if an HLA-identical sibling marrow donor was available (n = 40) and 20-25% if mismatched tissue was used. Data on the effect of bone transplantation on biochemical and clinical variables were available in 29 of the 63. 28 had a follow-up duration of 1.0-10.2 years; 1 patient died of disease progression in the first year after stable engraftment. 13 patients who had severe neurological symptoms at the time of transplantation showed disease progression. Engraftment of bone marrow in 5 patients with non-neuronopathic Gaucher's disease led to complete disappearance of symptoms. 11 patients had skeletal symptoms because of various mucopolysaccharidoses (MPSs). There was stabilisation of the skeletal lesions during the observation period of 1.4-6.4 years, but none of the patients showed significant regression of the skeletal symptoms. The visceral features (hepatosplenomegaly, cardiac hypertrophy, and upper airway obstruction) in these patients abated after transplantation. We could not evaluate the biochemical and clinical variables in 34 patients because of graft rejection, transplant-related mortality, or follow-up of less than 1 year. There were significant beneficial effects of bone marrow transplantation in patients with non-neuronopathic Gaucher's disease. Stabilisation of disease was observed in patients with MPS-I and MPS-II; this potential benefit needs to be confirmed by longer follow-up. Bone marrow transplantation was not effective if severe neurological symptoms were already present at the time of transplantation.
We report evidence of a dose responsive effect of enzyme replacement therapy in mucopolysaccharidosis type VI cats from birth, at the clinical, biochemical, and histopathological level. Cats treated with weekly, intravenous recombinant human N-acetylgalactosamine-4-sulfatase at 1 and 5 mg/kg, were heavier, more flexible, had greatly reduced or no spinal cord compression, and had almost normal urinary glycosaminoglycan levels. There was near normalization or complete reversal of lysosomal storage in heart valve, aorta, skin, dura, liver, and brain perivascular cells. No reduction in lysosomal vacuolation was observed in cartilage or cornea; however, articular cartilage was thinner and external ear pinnae were larger in some treated cats. Degenerative joint changes were not obviously delayed in treated cats. Skeletal pathology was reduced, with more normalized bone dimensions and with more uniform bone density and trabecular pattern clearly visible on radiographs by 5 to 6 mo; however, differences between 1 and 5 mg/kg dose rates were not clearly distinguishable. At a dose of 0.2 mg/kg, disease was not significantly altered in the majority of parameters examined. Lysosomal storage was present in all tissues examined in the midterm mucopolysaccharidosis type VI fetus and increased rapidly in extent and severity from birth.
The first report of a positive effect of allogeneic bone marrow transplantation (BMT) on the clinical course in a patient with a lysosomal storage disease was described in 1981. Since then, over 200 patients have been treated in this way but data are scarce and fragmentary. Allogeneic BMT involves replacement of the patient's haemopoietic system by that of a donor. The new cells that repopulate the body can correct the metabolic disturbance. Most experience with allogeneic BMT was gained in patients with mucopolysaccharidosis type I, metachromatic leukodystrophy and adrenoleukodystrophy. Allogeneic BMT reduces the amount of storage material in internal organs: skeletal abnormalities and neurological symptoms are at best stabilized. Transplantation-related mortality and morbidity are high. The applicability of allogeneic BMT is limited.
Alglucerase, a macrophage-targeted enzyme replacement therapy for Gaucher disease, has been successfully used for several years to improve clinical symptoms and reverse disease progression. As part of an immunosurveillance program, 1,122 Gaucher patients were monitored for antibody response to glucocerebrosidase, the active component of alglucerase. Seroconversion was detected in 142 patients (12.8%) by enzyme-linked immunosorbent assay (ELISA) and confirmed by radioimmunoprecipitation. The majority (75%) of the seroconverted population had no detectable levels of circulating inhibitory antibody as assessed by in vitro inhibition of enzymatic activity of the therapeutic molecule. Of the remaining patients with putative inhibitory antibodies, the majority had only low levels of serum inhibitory activity, which was transient. A very small number of patients were identified as developing true neutralizing antibodies, as defined by the development of antibodies that impacted clinical efficacy. Many of the patient antibody responses were also diminished with time. Eighty-two of the 142 seroconverted patients have stopped producing antibody to the molecule and appear tolerized. The mean time for humoral tolerization was 28 months from initiation of therapy. Of 64 seroconverted patients followed for at least 30 months of therapy, the tolerization rate was 93%. These results show that although 12.8% of the patients on therapy developed antibodies to the molecule, 90% of these patients became tolerized over time.
Enzyme-replacement therapy has been assessed as a treatment for patients who have mucopolysaccharidosis I (alpha-L-iduronidase deficiency). We aimed to investigate the humoral immune response to recombinant human alpha-L-iduronidase among these patients.
We characterised the antibody titres and specific linear sequence epitope reactivity of serum antibodies to alpha-L-iduronidase for ten patients with mucopolysaccharidosis I, at the start of treatment and after 6, 12, 26, 52, and 104 weeks. We compared the values for patients' samples with those for samples from normal human controls.
Before enzyme-replacement therapy, all patients had low serum antibody titres to recombinant human alpha-L-iduronidase that were within the control range. Five of the ten patients produced higher-than-normal titres of antibody to the replacement protein during the treatment course (serum antibody titres 130000-500000 and high-affinity epitope reactivity). However, by week 26, antibody reactivity was reduced, and by week 104 all patients had low antibody titres and only low-affinity epitope reactivity. Patients who had mucopolysaccharidosis I with antibody titres within the normal range at 6-12 weeks did not subsequently develop immune responses.
After 2 years of treatment, patients who initially had an immune reaction developed immune tolerance to alpha-L-iduronidase. This finding has positive implications for long-term enzyme-replacement therapy in patients who have mucopolysaccharidosis I.
To evaluate the safety and efficacy of weekly treatment with human recombinant N-acetylgalactosamine 4-sulfatase (rhASB) in humans with mucopolysaccharidosis type VI (MPS VI).
An ongoing Phase I/II, randomized, two-dose, double-blind study. Patients were randomized to weekly infusions of either high (1.0 mg/kg) or low (0.2 mg/kg) doses of rhASB. Six patients (3 male, 3 female; age 7-16 years) completed at least 24 weeks of treatment, five of this group have completed at least 48 weeks.
No drug-related serious adverse events, significant laboratory abnormalities, or allergic reactions were observed in the study. The high-dose group experienced a more rapid and larger relative reduction in urinary glycosaminoglycan that was sustained through week 48. Improvements in the 6-minute walk test were observed in all patients with dramatic gains in those walking <100 meters at baseline. Shoulder range of motion improved in all patients at week 48 and joint pain improved in patients with significant pain at baseline.
rhASB treatment was well-tolerated and reduced lysosomal storage as evidenced by a dose-dependent reduction in urinary glycosaminoglycan. Clinical responses were present in all patients, but the largest gains occurred in patients with advanced disease receiving high-dose rhASB.
The mucopolysaccharidoses The meta-bolic and molecular basis of inherited disease
- E Neufeld
- Muenzer
- Cr Scriver
- Al Beaudet
- D Valle
- Sly
- Ws
Neufeld E, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The meta-bolic and molecular basis of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p 3412–52.