The Experts below are selected from a list of 873 Experts worldwide ranked by ideXlab platform
William M. Pardridge - One of the best experts on this subject based on the ideXlab platform.
-
Insulin Receptor Antibody-Iduronate 2-Sulfatase Fusion Protein: Pharmacokinetics, Anti-Drug Antibody, and Safety Pharmacology in Rhesus Monkeys
Biotechnology and bioengineering, 2014Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, William M. PardridgeAbstract:Mucopolysaccharidosis (MPS) Type II is caused by mutations in the gene encoding the lysosomal enzyme, Iduronate 2-Sulfatase (IDS). The majority of MPSII cases affect the brain. However, enzyme replacement therapy with recombinant IDS does not treat the brain, because IDS is a large molecule drug that does not cross the blood-brain barrier (BBB). To enable BBB penetration, IDS has been re-engineered as an IgG-IDS fusion protein, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and the HIRMAb domain of the fusion protein acts as a molecular Trojan horse to ferry the fused IDS into brain from blood. The present study reports on the first safety pharmacology and pharmacokinetics study of the HIRMAb-IDS fusion protein. Juvenile male Rhesus monkeys were infused intravenously (IV) weekly for 26 weeks with 0, 3, 10, or 30 mg/kg of the HIRMAb-IDS fusion protein. The plasma clearance of the fusion protein followed a linear pharmacokinetics profile, which was equivalent either with measurements of the plasma concentration of immunoreactive HIRMAb-IDS fusion protein, or with assays of plasma IDS enzyme activity. Anti-drug antibody (ADA) titers were monitored monthly, and the ADA response was primarily directed against the variable region of the HIRMAb domain of the fusion protein. No infusion related reactions or clinical signs of immune response were observed during the course of the study. A battery of safety pharmacology, clinical chemistry, and tissue histopathology showed no signs of adverse events, and demonstrate the safety profile of chronic treatment of primates with 3–30 mg/kg weekly IV infusion doses of the HIRMAb-IDS fusion protein.
-
blood brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey
Bioconjugate Chemistry, 2013Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, Rachita K Sumbria, William M. PardridgeAbstract:Recombinant proteins are large molecule drugs that do not cross the blood-brain barrier (BBB). However, BBB-penetration of protein therapeutics is enabled by re-engineering the recombinant protein as IgG fusion proteins. The IgG domain is a monoclonal antibody (mAb) against an endogenous BBB receptor-mediated transport system, such as the human insulin receptor (HIR), and acts as a molecular Trojan horse to ferry the fused protein across the BBB. In the present study, a recombinant lysosomal enzyme, Iduronate 2-Sulfatase (IDS), is fused to the HIRMAb, and BBB penetration of the IDS alone vs the HIRMAb-IDS fusion protein is compared in the Rhesus monkey. Recombinant IDS and the HIRMAb-IDS fusion protein were radiolabeled with indirect iodination with the [125I]-Bolton-Hunter reagent and with direct iodination with Iodogen/[125I]-idodine. IDS and the HIRMAb-IDS fusion protein have comparable plasma pharmacokinetics and uptake by peripheral organs. IDS does not cross the BBB. The HIRMAb-IDS fusion protein cr...
-
selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species specific receptor targeted antibodies
Journal of Drug Targeting, 2012Co-Authors: Qinghui Zhou, Ruben J. Boado, William M. PardridgeAbstract:Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-Sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb-IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb-IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb-IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.
-
Brain-penetrating IgG-Iduronate 2-Sulfatase fusion protein for the mouse.
Drug metabolism and disposition: the biological fate of chemicals, 2011Co-Authors: Qinghui Zhou, Ruben J. Boado, Eric Ka-wai Hui, William M. PardridgeAbstract:Mucopolysaccharidosis (MPS) type II (Hunter's syndrome) is caused by mutations in the Iduronate 2-Sulfatase (IDS) fusion protein. MPS-II affects the brain, and enzyme replacement therapy is not effective in the brain, because the enzyme does not cross the blood-brain barrier. To treat mouse models of MPS-II with brain-penetrating IDS, the lysosomal enzyme was reengineered as an IgG-IDS fusion protein. The mature human IDS was fused to the carboxyl terminus of both heavy chains of the chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and the fusion protein is designated cTfRMAb-IDS. The purity and identity of the fusion protein was confirmed by electrophoresis and Western blotting with antibodies to mouse IgG and human IDS. The EC₅₀ of binding of the cTfRMAb-IDS fusion protein to the mouse TfR (0.85 ± 0.15 nM) was comparable to the EC₅₀ of binding of the cTfRMAb (0.78 ± 0.05 nM). The IDS enzyme activity of the cTfRMAb-IDS fusion protein was 126 ± 1 nmol · h⁻¹ · μg⁻¹ protein. After intravenous injection in the mouse, the cTfRMAb-IDS fusion protein was rapidly removed from plasma and distributed to tissues, including brain and spinal cord. The uptake of the fusion protein by brain or spinal cord was 1.3 ± 0.1 and 2.2 ± 0.2% injected dose/g, respectively, which is 100-fold greater than the brain uptake of IDS alone. This work shows that a lysosomal Sulfatase can be reengineered as an IgG-enzyme fusion protein that rapidly penetrates the brain after intravenous administration.
-
expression in cho cells and pharmacokinetics and brain uptake in the rhesus monkey of an igg Iduronate 2 Sulfatase fusion protein
Biotechnology and Bioengineering, 2011Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, Qinghui Zhou, William M. PardridgeAbstract:Sulfatases are potential therapeutic biopharmaceuticals, as mutations in Sulfatase genes leads to inherited disease. Mucopolysaccharidosis (MPS) Type II is caused by mutations in the lysosomal enzyme, Iduronate-2-Sulfatase (IDS). MPS-II affects the brain and enzyme replacement therapy is ineffective for the brain, because IDS does not cross the blood-brain barrier (BBB). To deliver IDS across the human BBB, the Sulfatase has been re-engineered as an IgG-Sulfatase fusion protein with a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the HIRMAb-IDS fusion protein acts as a molecular Trojan horse to ferry the fused IDS across the BBB. Chinese hamster ovary (CHO) cells were stably transfected to produce the HIRMAb-IDS fusion protein. The fusion protein was triaged to the lysosomal compartment of MPS-II fibroblasts based on confocal microscopy, and 300 ng/mL medium concentrations normalized IDS enzyme activity in the cells. The HIRMAb-IDS fusion protein was tritiated and injected intravenously into the adult Rhesus monkey at a low dose of 0.1 mg/kg. The IDS enzyme activity in plasma was elevated 10-fold above the endogenous level, and therapeutic plasma concentrations were generated in vivo. The uptake of the HIRMAb-IDS fusion protein in the brain was sufficiently high to produce therapeutic concentrations of IDS in the brain following IV administration of the fusion protein.
Ruben J. Boado - One of the best experts on this subject based on the ideXlab platform.
-
Insulin Receptor Antibody-Iduronate 2-Sulfatase Fusion Protein: Pharmacokinetics, Anti-Drug Antibody, and Safety Pharmacology in Rhesus Monkeys
Biotechnology and bioengineering, 2014Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, William M. PardridgeAbstract:Mucopolysaccharidosis (MPS) Type II is caused by mutations in the gene encoding the lysosomal enzyme, Iduronate 2-Sulfatase (IDS). The majority of MPSII cases affect the brain. However, enzyme replacement therapy with recombinant IDS does not treat the brain, because IDS is a large molecule drug that does not cross the blood-brain barrier (BBB). To enable BBB penetration, IDS has been re-engineered as an IgG-IDS fusion protein, where the IgG domain is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb crosses the BBB via receptor-mediated transport on the endogenous BBB insulin receptor, and the HIRMAb domain of the fusion protein acts as a molecular Trojan horse to ferry the fused IDS into brain from blood. The present study reports on the first safety pharmacology and pharmacokinetics study of the HIRMAb-IDS fusion protein. Juvenile male Rhesus monkeys were infused intravenously (IV) weekly for 26 weeks with 0, 3, 10, or 30 mg/kg of the HIRMAb-IDS fusion protein. The plasma clearance of the fusion protein followed a linear pharmacokinetics profile, which was equivalent either with measurements of the plasma concentration of immunoreactive HIRMAb-IDS fusion protein, or with assays of plasma IDS enzyme activity. Anti-drug antibody (ADA) titers were monitored monthly, and the ADA response was primarily directed against the variable region of the HIRMAb domain of the fusion protein. No infusion related reactions or clinical signs of immune response were observed during the course of the study. A battery of safety pharmacology, clinical chemistry, and tissue histopathology showed no signs of adverse events, and demonstrate the safety profile of chronic treatment of primates with 3–30 mg/kg weekly IV infusion doses of the HIRMAb-IDS fusion protein.
-
blood brain barrier molecular trojan horse enables imaging of brain uptake of radioiodinated recombinant protein in the rhesus monkey
Bioconjugate Chemistry, 2013Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, Rachita K Sumbria, William M. PardridgeAbstract:Recombinant proteins are large molecule drugs that do not cross the blood-brain barrier (BBB). However, BBB-penetration of protein therapeutics is enabled by re-engineering the recombinant protein as IgG fusion proteins. The IgG domain is a monoclonal antibody (mAb) against an endogenous BBB receptor-mediated transport system, such as the human insulin receptor (HIR), and acts as a molecular Trojan horse to ferry the fused protein across the BBB. In the present study, a recombinant lysosomal enzyme, Iduronate 2-Sulfatase (IDS), is fused to the HIRMAb, and BBB penetration of the IDS alone vs the HIRMAb-IDS fusion protein is compared in the Rhesus monkey. Recombinant IDS and the HIRMAb-IDS fusion protein were radiolabeled with indirect iodination with the [125I]-Bolton-Hunter reagent and with direct iodination with Iodogen/[125I]-idodine. IDS and the HIRMAb-IDS fusion protein have comparable plasma pharmacokinetics and uptake by peripheral organs. IDS does not cross the BBB. The HIRMAb-IDS fusion protein cr...
-
selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species specific receptor targeted antibodies
Journal of Drug Targeting, 2012Co-Authors: Qinghui Zhou, Ruben J. Boado, William M. PardridgeAbstract:Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood-brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-Sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb-IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb-IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb-IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.
-
Brain-penetrating IgG-Iduronate 2-Sulfatase fusion protein for the mouse.
Drug metabolism and disposition: the biological fate of chemicals, 2011Co-Authors: Qinghui Zhou, Ruben J. Boado, Eric Ka-wai Hui, William M. PardridgeAbstract:Mucopolysaccharidosis (MPS) type II (Hunter's syndrome) is caused by mutations in the Iduronate 2-Sulfatase (IDS) fusion protein. MPS-II affects the brain, and enzyme replacement therapy is not effective in the brain, because the enzyme does not cross the blood-brain barrier. To treat mouse models of MPS-II with brain-penetrating IDS, the lysosomal enzyme was reengineered as an IgG-IDS fusion protein. The mature human IDS was fused to the carboxyl terminus of both heavy chains of the chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and the fusion protein is designated cTfRMAb-IDS. The purity and identity of the fusion protein was confirmed by electrophoresis and Western blotting with antibodies to mouse IgG and human IDS. The EC₅₀ of binding of the cTfRMAb-IDS fusion protein to the mouse TfR (0.85 ± 0.15 nM) was comparable to the EC₅₀ of binding of the cTfRMAb (0.78 ± 0.05 nM). The IDS enzyme activity of the cTfRMAb-IDS fusion protein was 126 ± 1 nmol · h⁻¹ · μg⁻¹ protein. After intravenous injection in the mouse, the cTfRMAb-IDS fusion protein was rapidly removed from plasma and distributed to tissues, including brain and spinal cord. The uptake of the fusion protein by brain or spinal cord was 1.3 ± 0.1 and 2.2 ± 0.2% injected dose/g, respectively, which is 100-fold greater than the brain uptake of IDS alone. This work shows that a lysosomal Sulfatase can be reengineered as an IgG-enzyme fusion protein that rapidly penetrates the brain after intravenous administration.
-
expression in cho cells and pharmacokinetics and brain uptake in the rhesus monkey of an igg Iduronate 2 Sulfatase fusion protein
Biotechnology and Bioengineering, 2011Co-Authors: Ruben J. Boado, Eric Ka-wai Hui, Qinghui Zhou, William M. PardridgeAbstract:Sulfatases are potential therapeutic biopharmaceuticals, as mutations in Sulfatase genes leads to inherited disease. Mucopolysaccharidosis (MPS) Type II is caused by mutations in the lysosomal enzyme, Iduronate-2-Sulfatase (IDS). MPS-II affects the brain and enzyme replacement therapy is ineffective for the brain, because IDS does not cross the blood-brain barrier (BBB). To deliver IDS across the human BBB, the Sulfatase has been re-engineered as an IgG-Sulfatase fusion protein with a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the HIRMAb-IDS fusion protein acts as a molecular Trojan horse to ferry the fused IDS across the BBB. Chinese hamster ovary (CHO) cells were stably transfected to produce the HIRMAb-IDS fusion protein. The fusion protein was triaged to the lysosomal compartment of MPS-II fibroblasts based on confocal microscopy, and 300 ng/mL medium concentrations normalized IDS enzyme activity in the cells. The HIRMAb-IDS fusion protein was tritiated and injected intravenously into the adult Rhesus monkey at a low dose of 0.1 mg/kg. The IDS enzyme activity in plasma was elevated 10-fold above the endogenous level, and therapeutic plasma concentrations were generated in vivo. The uptake of the HIRMAb-IDS fusion protein in the brain was sufficiently high to produce therapeutic concentrations of IDS in the brain following IV administration of the fusion protein.
Chihkuang Chuang - One of the best experts on this subject based on the ideXlab platform.
-
taiwan national newborn screening program by tandem mass spectrometry for mucopolysaccharidoses types i ii and vi
The Journal of Pediatrics, 2019Co-Authors: Minju Chan, Michael H. Gelb, Hsuanchieh Liao, Chihkuang Chuang, Meiying Liu, Hsiaojan Chen, Shumin Kao, Hsiangyu Lin, Youhsin Huang, Arun KumarAbstract:Objective To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. Study design More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. Results Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic Iduronate-2-Sulfatase mutations, and 1 newborn was a carrier of an arylSulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. Conclusions The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible.
-
detection of hunter syndrome mucopolysaccharidosis type ii in taiwanese biochemical and linkage studies of the Iduronate 2 Sulfatase gene defects in mps ii patients and carriers
Clinica Chimica Acta, 2006Co-Authors: Shuanpei Lin, Chihkuang Chuang, Hsiangyu Lin, Juihung Chang, Guey Jen Leechen, Dar Shong LinAbstract:Abstract Background Hunter syndrome (mucopolysaccharidosis type II) is an X-linked recessive lysosomal storage disease caused by a defect of the Iduronate-2-Sulfatase (IDS) gene. The result is impaired IDS enzyme function. Methods To characterize the biochemical and molecular defects in IDS-deficient patients and their families, we measured IDS enzyme activity by fluorimetric enzyme assay and identified the IDS gene mutations in 14 unrelated Taiwanese patients with varying clinical phenotypes. In addition, haplotype analysis was also performed. Results Three novel (IVS2 + 1G > C, 1055del12, and G489D) and 7 previously reported (N63K, P228L, K347E, R468Q, R468W, I485R, and 1241delAG) mutations were found. Together R468Q and R468W account for 42.8% mutations found in our patients. Haplotype analysis using IDS flanking markers DXS1113 and DXS1123 revealed that the unrelated R468Q alleles were independent in origin whereas the unrelated R468W alleles are probably of the same origin. The R468Q mutation in patient 1150 and I485R mutation in patient 710 occurred de novo in male meioses. Once the mutation in a family was identified, restriction analysis was also performed for rapid diagnosis of female carriers in 8 families. Leukocyte IDS measurement revealed significantly wide range of IDS activity in normal controls and MPS II carriers (19.2∼70.6 vs. 8.4∼26.6 nmol/h/mg cell protein). The average leukocyte IDS activity of normal controls (n = 43) was 43.9 ± 13.3 nmol/h/mg protein, whereas patients with MPS II (n = 14) had Conclusion Due to a small overlapping range of normal and carriers, the level of enzyme activity cannot be used alone for carrier detection.
Joseph Muenzer - One of the best experts on this subject based on the ideXlab platform.
-
neurodevelopmental status and adaptive behavior of pediatric patients with hunter syndrome a longitudinal observational study
Molecular Genetics and Metabolism, 2019Co-Authors: Joseph Muenzer, Paul Harmatz, Barbara K. Burton, Hernan Amartino, Simon Jones, Luis Gonzalez Gutierrezsolana, Matilde Ruizgarcia, David AlexanderianAbstract:Two-thirds of patients with mucopolysaccharidosis type II (MPS II Hunter syndrome), a rare lysosomal disease characterized by Iduronate-2-Sulfatase deficiency, have cognitive impairment. This observational, prospective, longitudinal study (NCT01822184) assessed cognitive status and adaptive behavior in patients aged 2− 70 (n=26) were −2.4 (p=0.5657) at month 12 and −7.4 (p=0.1461) at month 24. Similarly, for VABS-II ABC scores, differences in LSM changes from baseline between the GCA subgroups (≤70/>70) were −1.9 (p=0.5545) at month 12 and 0.3 (p=0.9484) at month 24. Overall, cognitive ability and adaptive behavior in the pediatric MPS II population who completed this study remained relatively stable over 24 months. However, some patients experienced a rapid decline in cognitive ability, while others retained stable, but impaired, cognitive function. Shire funded this study and medical writing support.
-
Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome
Genetics in Medicine, 2011Co-Authors: Joseph Muenzer, Paul Harmatz, Michael Beck, Roberto Giugliani, Rick Martin, Uma Ramaswami, Ashok Vellodi, James E Wraith, Maureen Cleary, Muge Gucsavas-calikogluAbstract:Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human Iduronate-2-Sulfatase) in patients with Hunter syndrome. Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. Conclusions: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.
-
recognition and diagnosis of mucopolysaccharidosis ii hunter syndrome
Pediatrics, 2008Co-Authors: Rick A Martin, Paul Harmatz, Veronica Munoz, Michael Beck, Roberto Giugliani, Joseph MuenzerAbstract:Mucopolysaccharidosis II, also known as Hunter syndrome, is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme Iduronate-2-Sulfatase, which catalyzes a step in the catabolism of glycosaminoglycans. In patients with mucopolysaccharidosis II, glycosaminoglycans accumulate within tissues and organs, contributing to the signs and symptoms of the disease. Mucopolysaccharidosis II affects multiple organs and physiologic systems and has a variable age of onset and variable rate of progression. Common presenting features include excess urinary glycosaminoglycan excretion, facial dysmorphism, organomegaly, joint stiffness and contractures, pulmonary dysfunction, myocardial enlargement and valvular dysfunction, and neurologic involvement. In patients with neurologic involvement, intelligence is impaired, and death usually occurs in the second decade of life, whereas those patients with minimal or no neurologic involvement may survive into adulthood with normal intellectual development. Enzyme replacement therapy has emerged as a new treatment for mucopolysaccharidosis disorders, including Hunter syndrome. The purpose of this report is to provide a concise review of mucopolysaccharidosis II for practitioners with the hope that such information will help identify affected boys earlier in the course of their disease.
-
the characterization of a murine model of mucopolysaccharidosis ii hunter syndrome
Journal of Inherited Metabolic Disease, 2007Co-Authors: A Garcia, J Pan, J C Lamsa, Joseph MuenzerAbstract:Mucopolysaccharidosis II (MPS II, Hunter syndrome in humans) is an X-linked inherited lysosomal storage disease caused by a deficiency in the lysosomal enzyme Iduronate-2-Sulfatase (I2S). I2S catalyses a step in the catabolism of glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate, and when it is deficient or absent GAGs accumulate in tissues and organs. Male knockout mice (IdS-KO), which lack the gene coding for I2S, exhibit many of the characteristics seen in the human disease. Compared to wild-type control mice, urine GAG excretion was elevated at 4 weeks of age and remained high throughout the lifespan, and tissue GAG levels were elevated as early as 7 weeks of age. Liver, spleen and other organs were significantly larger in the IdS-KO mice than in the wild-type. Radiographic examination revealed sclerosis and enlargement of the skull at 4 weeks of age and appendicular bone enlargement at 10–13 weeks of age. Micro CT scans showed severe periosteal bone formation at the lateral aspect of the distal tibia and calcification of the calcaneus tendon. This model was used in the development of idursulfase for treatment of MPS II and may continue to be useful in the evaluation of treatment strategies of this chronic and progressive disorder.
-
a phase i ii clinical trial of enzyme replacement therapy in mucopolysaccharidosis ii hunter syndrome
Molecular Genetics and Metabolism, 2007Co-Authors: Joseph Muenzer, Muge Gucsavascalikoglu, Shawn E Mccandless, Thomas J Schuetz, Alan KimuraAbstract:Abstract Objective To evaluate the safety and explore the efficacy of idursulfase (recombinant human Iduronate-2-Sulfatase) treatment for mucopolysaccharidosis II (MPS II). Study design Twelve patients were enrolled into a randomized, double-blind, placebo-controlled trial for 24 weeks followed by an open-label extension study. Three groups of 4 patients were enrolled sequentially, with 3 patients in each group receiving idursulfase and 1 patient receiving placebo. The first group received idursulfase at 0.15 mg/kg infused every other week with the 2nd and 3rd groups receiving 0.5 and 1.5 mg/kg, respectively. After 24 weeks the placebo-treated patients were changed to idursulfase at the dose of their group. The primary endpoint was a change from baseline in urinary excretion of glycosaminoglycans. Results were pooled for analysis by ANOVA and compared to baseline. Results Urinary glycosaminoglycans were reduced within 2 weeks of initiating idursulfase and were decreased 49% after 48 weeks of treatment (P Conclusions This study describes the first experience with enzyme replacement therapy for the treatment of patients with MPS II. Idursulfase was generally well tolerated and was associated with reductions in urine glycosaminoglycans levels and organ size, as well as an increased 6-minute walk test distance.
Michael H. Gelb - One of the best experts on this subject based on the ideXlab platform.
-
taiwan national newborn screening program by tandem mass spectrometry for mucopolysaccharidoses types i ii and vi
The Journal of Pediatrics, 2019Co-Authors: Minju Chan, Michael H. Gelb, Hsuanchieh Liao, Chihkuang Chuang, Meiying Liu, Hsiaojan Chen, Shumin Kao, Hsiangyu Lin, Youhsin Huang, Arun KumarAbstract:Objective To evaluate the initial cutoff values, rates of screen positives, and genotypes for the large-scale newborn screening program for multiple mucopolysaccharidoses (MPS) in Taiwan. Study design More than 100 000 dried blood spots were collected consecutively as part of the national Taiwan newborn screening programs. Enzyme activities were measured by tandem mass spectrometry from dried blood spot punches. Genotypes were obtained when a second newborn screening specimen again had a decreased enzyme activity. Additional clinical evaluation was then initiated based on enzyme activity and/or genotype. Results Molecular genetic analysis for cases with low enzyme activity revealed 5 newborns with pathogenic alpha-L-iduronidase mutations, 3 newborns with pathogenic Iduronate-2-Sulfatase mutations, and 1 newborn was a carrier of an arylSulfatase B mutation. Several variants of unknown pathogenic significance were also identified, most likely causing pseudodeficiency. Conclusions The highly robust tandem mass spectrometry-based enzyme assays for MPS-I, MPS-II, and MPS-VI allow for high-throughput newborn screening for these lysosomal storage disorders. Optimized cutoff values combined with second tier testing could largely eliminate false-positive results. Accordingly, newborn screening for these lysosomal storage disorders is possible.
-
Improved Reagents for Newborn Screening of Mucopolysaccharidosis Types I, II, and VI by Tandem Mass
2016Co-Authors: Naveen Kumar Chennamaneni, Ronald C Scott, Mariana Barcenas, Arun Babu Kumar, Michael H. GelbAbstract:ABSTRACT: Tandem mass spectrometry for the multiplex and quantitative analysis of enzyme activities in dried blood spots on newborn screening cards has emerged as a powerful technique for early assessment of lysosomal storage diseases. Here we report the design and process-scale synthesis of substrates for the enzymes α-L-iduronidase, Iduronate-2-Sulfatase, and N-acetylgalactosamine-4-Sulfatase that are used for newborn screening of mucopolysaccharidosis types I, II, and VI. The products contain a bisamide unit that is hypothesized to readily protonate in the gas phase, which improves detection sensitivity by tandem mass spectrometry. The products contain a benzoyl group, which provides a useful site for inexpensive deuteration, thus facilitating the prepara-tion of internal standards for the accurate quantification of enzymatic products. Finally, the reagents are designed with ease of synthesis in mind, thus permitting scale-up preparation to support worldwide newborn screening of lysosomal storage diseases
-
improved reagents for newborn screening of mucopolysaccharidosis types i ii and vi by tandem mass spectrometry
Analytical Chemistry, 2014Co-Authors: Naveen Kumar Chennamaneni, František Tureček, Ronald C Scott, Arun Kumar, Mariana Barcenas, Zdenek Spacil, Michael H. GelbAbstract:Tandem mass spectrometry for the multiplex and quantitative analysis of enzyme activities in dried blood spots on newborn screening cards has emerged as a powerful technique for early assessment of lysosomal storage diseases. Here we report the design and process-scale synthesis of substrates for the enzymes α-l-iduronidase, Iduronate-2-Sulfatase, and N-acetylgalactosamine-4-Sulfatase that are used for newborn screening of mucopolysaccharidosis types I, II, and VI. The products contain a bisamide unit that is hypothesized to readily protonate in the gas phase, which improves detection sensitivity by tandem mass spectrometry. The products contain a benzoyl group, which provides a useful site for inexpensive deuteration, thus facilitating the preparation of internal standards for the accurate quantification of enzymatic products. Finally, the reagents are designed with ease of synthesis in mind, thus permitting scale-up preparation to support worldwide newborn screening of lysosomal storage diseases. The ne...
-
tandem mass spectrometry for the direct assay of lysosomal enzymes in dried blood spots application to screening newborns for mucopolysaccharidosis ii hunter syndrome
Analytical Chemistry, 2010Co-Authors: Brian J Wolfe, Martin Sadilek, František Tureček, Sophie Blanchard, Ronald C Scott, Michael H. GelbAbstract:We have developed a tandem mass spectrometry based assay of Iduronate-2-Sulfatase (IdS) activity for the neonatal detection of mucopolysaccharidosis II (MPS-II, Hunter Syndrome). The assay uses a newly designed synthetic substrate (IdS-S) consisting of α-l-Iduronate-2-sulfate, which is glycosidically conjugated to a coumarin and a linker containing a tert-butyloxycarbamido group. A short synthesis of the substrate has been developed that has the potential of being scaled to multigram quantities. Sulfate hydrolysis of IdS-S by IdS found within a 3 mm dried blood spot specifically produces a nonsulfated product (IdS-P) which is detected by electrospray tandem mass spectrometry and quantified using a deuterium-labeled internal standard, both carried out in positive ion mode. Analysis of DBS from 75 random human newborns showed IdS activities in the range of 4.8−16.2 (mean 9.1) μmol/(h L of blood), which were clearly distinguished from the activities measured for 14 MPS-II patients at 0.17−0.52 (mean 0.29) μm...
