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PubMed1976

Detection of the carrier state of Hurler's syndrome by assay of alpha-L-iduronidase in leukocytes.

The mean specific activity of alph-L-iduronidase in leukocytes from six obligate heterozygotes for Hurler's syndrome was found to be slightly less than one-half of the mean in normal controls; no overlap of normal and known heterozygote values was encountered. The assay has been applied with success to six potential heterozygotes, siblings of a child with Hurler's syndrome. Thus heterozygote detection of Hurler's syndrome is clearly possible; this finding, as well as the ready availability of leukocytes for screening tests, recommends their use for examination of potential carrier status in this disorder.

Adult↗
PubMed1984

Specific inhibition of human beta-D-glucuronidase and alpha-L-iduronidase by a trihydroxy pipecolic acid of plant origin.

The glucuronic acid analogue of 1-deoxynojirimycin, 2(S)-carboxy-3(R), 4(R), 5(S)-trihydroxypiperidine, recently isolated from seeds of Baphia racemosa, is a novel specific inhibitor of human liver beta-D-glucuronidase and alpha-L-iduronidase. No other glycosidases are inhibited. The inhibition of beta-D-glucuronidase is competitive, with a Ki of 8 X 10(-5) M and is pH-dependent. This inhibitor may be useful to induce a mucopolysaccharidosis or to investigate the function of microsomal beta-D-glucuronidase.

Binding, Competitive↗
PubMed1990

Orofacial features of Scheie (Hurler-Scheie) syndrome (alpha-L-iduronidase deficiency).

Scheie syndrome is a rare inborn error of metabolism, a mucopolysaccharidosis in which deficiency of the lysosomal enzyme alpha-L-iduronidase leads to tissue accumulation of mucopolysaccharides. Scheie syndrome is a forme fruste of Hurler syndrome (gargoylism), and some patients have the phenotype of Hurler-Scheie compound syndrome. The craniofacial abnormalities include coarse facies, mandibular condylar hypoplasia, retarded tooth eruption, and cystic jaw radiolucencies--particularly about the molars. Corneal clouding may lead to blindness but, in contrast to some other mucopolysaccharidoses, mental handicap is rare in Scheie syndrome. Cardiac valve incompetence is common, as are recurrent respiratory infections. Two brothers with Hurler-Scheie syndrome are presented and the oral and systemic complications each patient had described. The syndrome is discussed with particular reference to the orofacial features.

Adolescent↗
PubMed1992

Structure and sequence of the human alpha-L-iduronidase gene.

In humans, a deficiency of the lysosomal hydrolase alpha-L-iduronidase (IDUA;EC 3.2.1.76) results in the lysosomal storage of the glycosaminoglycans heparan sulfate and dermatan sulfate, thereby causing the lysosomal storage disorder mucopolysaccharidosis type I. The gene for IDUA is split into 14 exons spanning approximately 19 kb. We report the sequence of two non-contiguous segments of the IDUA gene, one 1.8-kb segment containing exons 1 and 2 and surrounding sequences and a second segment of 4.5 kb containing the last 12 exons. The potential promoter for IDUA has only GC box type consensus sequences consistent with a housekeeping promoter and is bounded by an Alu repeat sequence. The first two exons of IDUA are separated by an intron of 566 bp, then there is a large intron of approximately 13 kb, and the last 12 exons are clustered within 4.5 kb. No consensus polyadenylation signal was found in the 3' untranslated region, although two variant polyadenylation signals are proposed.

Base Sequence↗
PubMed2004

Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).

OBJECTIVE: To confirm the efficacy and safety of recombinant human alpha-L-iduronidase (laronidase) in patients with mucopolysaccharidosis I (MPS I). STUDY DESIGN: This was a randomized, double-blinded, multinational study of 45 patients with MPS I administered 100 U/kg (0.58 mg/kg) laronidase, or placebo intravenously weekly for 26 weeks. The coprimary efficacy end points compared the median change from baseline to week 26 between groups in percentage of predicted normal forced vital capacity (FVC) and in 6-minute walk test (6MWT) distance through the use of the Wilcoxon rank sum test. RESULTS: The laronidase (n=22) and placebo (n=23) groups had similar baseline characteristics. After 26 weeks, patients receiving laronidase compared with placebo showed mean improvements of 5.6 percentage points in percent of predicted normal FVC (median, 3.0; P=.009) and 38.1 meters in 6MWT distance (median, 38.5; P=.066; P=.039, analysis of covariance). Laronidase also significantly reduced hepatomegaly and urinary glycosaminoglycans, and, in more severely affected patients, improved sleep apnea/hypopnea and shoulder flexion. Laronidase was well-tolerated. Nearly all patients receiving enzyme had development of IgG antibodies, without apparent clinical effects. CONCLUSIONS: In patients with MPS I, laronidase significantly improves respiratory function and physical capacity, reduces glycosaminoglycan storage, and has a favorable safety profile.

Adolescent↗
PubMed2005

A homology model for human alpha-l-iduronidase: insights into human disease.

Genotype-phenotype correlations in genetic diseases for which missense mutations lead to disease remain a challenge. This is particularly true for diseases caused by alterations of proteins for which no three-dimensional structure is available. One such disease is Mucopolysaccharidosis type I, a disorder arising from a lack of activity of the lysosomal enzyme alpha-l-iduronidase (IDUA, EC 3.2.1.76). This deficiency compromises the degradation pathway of glycosaminoglycans such as heparan sulfate and dermatan sulfate, leading to substrate accumulation, which ultimately results in a multisystem disorder. Patients with IDUA deficiency have a wide spectrum of disease ranging from an early onset, rapidly progressive form leading to death in the first decade of life, to an attenuated disease which manifests in adolescence and leads to progressive joint and cardiac disease but is associated with a normal life span. Many patients fit into a disease phenotype intermediate to these extremes. While a number of point mutations have been described as leading to varying degrees of disease severity, a structural basis for these genotype-phenotype correlations has not been available owing to the lack of a three-dimensional structure for IDUA. A homology model for the IDUA enzyme was constructed based on the recently solved crystal structure of the beta-xylosidase from Thermoanaerobacterium saccharolyticum (XyTS, EC 3.2.1.37), both of which belong to the same sequence-related family (CAZY family 39). This model provides insights into why certain point mutations produce severely misfolded proteins and thus lead to severe disease, and why other mutations produce proteins with only minor structural perturbations and therefore the attenuated form of the disease.

Amino Acid Sequence↗
PubMed2005

Penetration, diffusion, and uptake of recombinant human alpha-L-iduronidase after intraventricular injection into the rat brain.

Central nervous system disease can have devastating consequences in the severe or Hurler form of mucopolysaccharisosis I (MPS I). Intravenously administered recombinant human alpha-L-iduronidase (rhIDU) is not expected to reach and treat the brain disease due to the blood-brain barrier. To determine whether administration of rhIDU into the cerebrospinal fluid could successfully treat the brain, we studied intraventricular administration of rhIDU in rats. RhIDU was stereotactically administered directly to the lateral ventricle of the intact rat brain and the brain tissues assessed by enzyme assays, immunofluorescence and confocal microscopy 30 min, 24 h, or 7 days later. Quantitation of activity revealed that rhIDU was widely distributed throughout the brain following injection into the lateral ventricle, with activities increased by a factor of 3.3 higher than control in most samples 30 min-24 h after injection and highest levels on the side of injection. The enzyme crossed the ependymal lining of the ventricle and entered neurons into lysosomal-like vesicles. The enzyme was able to diffuse through brain tissue as demonstrated by a decreasing signal gradient from 0.2 to 4.8 mm from the ventricle surface. The largest amount of rhIDU, as detected by immunostaining, was observed 24 h after injection and decreased approximately 50% during the first 7 days. Although the immunostaining decreased with time, specific vesicular staining was still detectable 28 days after injection. The data suggest that rhIDU given into the ventricle can diffuse, penetrate at least several millimeters of brain tissue and be taken up into neurons and glial cells.

Animals↗
PubMed2006

alpha-L-Iduronidase transport in neurites.

Effective therapeutic strategies for mucopolysaccharidosis type I (MPSI) rely on mannose-6-phosphate receptor-mediated uptake of extracellular alpha-l-iduronidase (IDUA), the missing lysosomal enzyme in this disease, by deficient cells. Intravenously infused recombinant human IDUA does not reach the central nervous system, whereas neuropathology and neurological manifestations are prominent in Hurler syndrome, the most severe and most frequent form of MPSI. The creation of a single intracerebral source of IDUA by gene therapy was proved efficient to deliver enzyme throughout the brain of MPSI mice. IDUA spreading far beyond areas where the enzyme was synthesized suggested transport along neuronal processes. To examine the mechanisms of IDUA spreading in the brain, we constructed a chimeric protein in which GFP is fused at the C-terminus of IDUA. The fusion protein was expressed in rat primary neurons using lentivirus vectors. Fluorescent IDUA retained full catalytic activity including on natural substrates, interacted with mannose-6-phosphate receptors and was appropriately addressed to lysosomes. Fluorescent vesicles were broadly distributed over neuronal soma and processes. Time-lapse fluorescent video-microscopy showed that 54% of fluorescent vesicles exhibited either retrograde or anterograde displacements along neurites. Most moving organelles showed complex movements with frequent direction changes and arrests. Motility depended on microtubule integrity. Efficient axono-dendritic transport of IDUA provides a rationale for gene therapy based on the release of therapeutic enzyme at discrete locations within the central nervous system of patients with severe form of MPSI.

Animals↗
PubMed2006

Effect of neonatal administration of a retroviral vector expressing alpha-L-iduronidase upon lysosomal storage in brain and other organs in mucopolysaccharidosis I mice.

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program cells to secrete IDUA modified with mannose 6-phosphate (M6P), and enzyme could be taken up by other cells via the M6P receptor. We previously reported that newborn MPS I mice that were injected intravenously with 10(9) (high-dose) or 10(8) (low-dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA achieved stable levels of IDUA activity in serum and had reduced disease in heart, eye, ear, and bone in a dose-dependent fashion. However, the dose required for improvement in manifestations of disease in other organs was not reported. High-dose and low-dose RV mice with an average serum IDUA activity of 1037+/-90 U/ml (471-fold normal) and 43+/-12 U/ml (20-fold normal), respectively, had complete correction of biochemical and pathological evidence of disease in the liver, spleen, kidney, and small intestines. Although mice that received high-dose RV had complete correction of lysosomal storage in thymus, ovary, lung, and testis, correction in these organs was only partial for those that received low-dose RV. Storage in brain was almost completely corrected with high-dose RV, but was not improved with low-dose RV. The correction of disease in brain may be due to diffusion of enzyme from blood. We conclude that high-dose RV prevents biochemical and pathological manifestations of disease in all organs in MPS I mice including brain.

Animals↗
PubMed2004

Correction of metabolic, craniofacial, and neurologic abnormalities in MPS I mice treated at birth with adeno-associated virus vector transducing the human alpha-L-iduronidase gene.

Murine models of lysosomal storage diseases provide an opportunity to evaluate the potential for gene therapy to prevent systemic manifestations of the disease. To determine the potential for treatment of mucopolysaccharidosis type I using a gene delivery approach, a recombinant adeno-associated virus (AAV) vector, vTRCA1, transducing the human iduronidase (IDUA) gene was constructed and 1 x 10(10) particles were injected intravenously into 1-day-old Idua(-/-) mice. High levels of IDUA activity were present in the plasma of vTRCA1-treated animals that persisted for the 5-month duration of the study, with heart and lung of this group demonstrating the highest tissue levels of gene transfer and enzyme activity overall. vTRCA1-treated Idua(-/-) animals with measurable plasma IDUA activity exhibited histopathological evidence of reduced lysosomal storage in a number of tissues and were normalized with respect to urinary GAG excretion, craniofacial bony parameters, and body weight. In an open field test, vTRCA1-treated Idua(-/-) animals exhibited a significant reduction in total squares covered and a trend toward normalization in rearing events and grooming time compared to control-treated Idua(-/-) animals. We conclude that AAV-mediated transduction of the IDUA gene in newborn Idua(-/-) mice was sufficient to have a major curative impact on several of the most important parameters of the disease.

Animals↗
PubMed2001

Detection of mucopolysaccharidosis type I heterozygotes on the basis of the biochemical properties of plasma alpha-L-iduronidase.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a disease caused by deficiency of the enzyme alpha-L-iduronidase (IDUA). Since no treatment is currently available for this disorder, the detection of heterozygotes is very important for genetic counseling and prenatal diagnosis. The objective of the present study was to characterize plasma IDUA from MPS I heterozygotes in an attempt to distinguish it from that of normal individuals. METHODS: We determined the optimum pH, Km, Vmax and Calpha (Vmax/Km) of the reaction and the thermal stability of IDUA at 50 degrees C. RESULTS: MPS I heterozygotes can be separated from normal individuals on the basis of Km, Calpha and thermal stability of the enzyme. CONCLUSIONS: Taking into consideration the clinical status of the homozygous offspring, we were able to subdivide the MPS I heterozygotes into various subgroups (Hurler, Scheie or Hurler/Scheie compound), and verified that the Hurler subgroup had a lower optimum pH for IDUA activity than controls and other MPS I subgroups, and that all MPS I subgroups had higher Km and lower Calpha when compared to controls.

Enzyme Stability↗
PubMedDate not supplied

Detection of mucopolysaccharidosis type I heterozygotes based on the biochemical characteristics of leukocyte alpha-L-iduronidase.

BACKGROUND: In the present study, we biochemically characterized the enzyme alpha-L-iduronidase (IDUA) of leukocytes from normal individuals and from mucopolysaccharidosis I (MPS I) heterozygotes, and compared these characteristics to discriminate for inclusion into two different groups. METHODS: We fluorimetrically measured IDUA activity in leukocytes using 4-methylumbelliferyl-alpha-L-iduronide as an artificial substrate. Optimum pH, Km, Vmax, and thermostability of the enzyme at 50 degrees C were determined. RESULTS: Based on leukocyte IDUA activity, we divided the heterozygotes into two groups, one (group 1) with activity below that detected in controls, and the other with activity similar to that of normal individuals (group 2). The optimum pH for IDUA was 2.7 for normal individuals and 2.6-2.8 for heterozygotes. With respect to Km, there was a difference only between the value for normal IDUA (0.60 mM) and the value for group 2 (0.38 mM), while group 1 showed a statistically similar value (0.49 mM). The Vmax of the reaction was discriminated in the three groups in a highly effective manner. The IDUA of normal individuals had a higher Vmax (60.98 nmoL/h x mg protein) than the enzyme of group 1 heterozygotes (28.66 nmoL/h x mg protein) and the enzyme of group 2 (31.78 nmoL/h x mg protein). When the IDUA from the three groups was pre-incubated at 50 degrees C, we observed that the IDUA of both group 1 and group 2 was significantly more thermostable than the IDUA of normal individuals. CONCLUSIONS: Determination of IDUA activity alone is not sufficient to discriminate between MPS I heterozygotes and normal individuals because a considerable overlap occurs between them. Our study showed that leukocyte IDUA from MPS I heterozygotes differed from the normal enzyme in terms of optimum pH, Km, and Vmax of the reaction and thermostability at 50 degrees C. These parameters provide a simple and reliable tool for the detection of carriers for MPS I.

Child↗
PubMed2000

Chemoenzymatic preparation of dermatan sulfate oligosaccharides as arylsulfatase B and alpha-L-iduronidase substrates.

Dermatan sulfate was partially depolymerized with chondroitin ABC lyase to obtain an oligosaccharide mixture from which an unsaturated disulfated tetrasaccharide was purified and characterized using nuclear magnetic resonance spectroscopy and electrospray ionization mass spectrometry. Chemical removal of the unsaturated uronate residue with mercuric acetate, followed by de-4-O-sulfation with arylsulfatase B (N-acetylgalactosamine 4-sulfatase) and N- acetylhexosaminidase catalyzed removal of the 2-acetamido-2-deoxy-D-galactospyranosyl residue at the non-reducing end afforded a monosulfated disaccharide of the structure alpha-L-idopyranosyluronic acid (1-->3)-alpha,beta-D-2-acetamido-2-deoxy-4-O-sulfo galactopyranose. This monosulfated disaccharide serves as a substrate for mammalian alpha-L-iduronidase as demonstrated using fluorophore assisted carbohydrate electrophoresis.

Animals↗
PubMed1999

Mucopolysaccharidosis type I: characterization of novel mutations affecting alpha-L-iduronidase activity.

alpha-L-Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I, MPS I) involves a broad spectrum of clinical severity ranging from a severe Hurler syndrome through an intermediate Hurler Scheie syndrome to a mild Scheie syndrome. To date, a number of mutations of the IDUA gene are known in Hurler syndrome, but only a few in Hurler Scheie or Scheie syndrome. The characterization of novel mutations in two patients with the Hurler-Scheie syndrome is reported on. The novel R619G mutation (C-G transversion in codon 619) was apparently homozygous. In transfected COS-7 cells, R619G caused significant reduction in enzyme activity (1.5% of normal activity), although it did not cause significant reduction in IDUA mRNA or protein level. Conversely, the previously described homozygous T364M mutation (C-T transition in codon 364) caused a decrease in the level of IDUA mRNA. Studies inhibiting RNA synthesis with actinomycin D or inhibiting protein synthesis with cycloheximide demonstrate that the decrease in the latter mutation is attributable to an increased rate of mRNA decay. By examining the stability of IDUA mRNA and protein, studies provide better insight into the effect of mutation on IDUA activity.

Amino Acid Sequence↗
PubMed2000

Identification and characterization of -3c-g acceptor splice site mutation in human alpha-L-iduronidase associated with mucopolysaccharidosis type IH/S.

DNA screening for mutations in the alpha-L-iduronidase (IDUA) gene was performed in a Chinese mucopolysaccharidosis type IH/S patient. The patient had two different mutations: the maternal allele has L346R (t-g transversion in codon 346) and the paternal allele has 388-3c-g (c-g transversion at position -3 of the 3' splice site of intron 2). In transfected COS-7 cells, L346R showed no appreciable IDUA activity (0.4% of normal activity), although it did not cause an apparent reduction in IDUA mRNA or protein level. The 388-3c-g mutation profoundly affects normal splicing leading to a very unstable mRNA. Expression of the IDUA cDNA containing the mutated acceptor splice site showed trace amounts of enzyme activity (1.6% of normal activity). The results provide further support for the importance of cytosine at the -3 position in RNA processing.

Animals↗
PubMed2000

Measurements from normal umbilical cord blood of four lysosomal enzymatic activities: alpha-L-iduronidase (Hurler), galactocerebrosidase (globoid cell leukodystrophy), arylsulfatase A (metachromatic leukodystrophy), arylsulfatase B (Maroteaux-Lamy).

Umbilical cord blood (UCB) has received increasing attention as a source of unrelated hematopoietic stem cells for transplantation. Lysosomal diseases have been effectively treated and normal enzymatic activity has occurred subsequent to engraftment using UCB. The use of donor cells with normal amounts of enzyme, rather than those from carriers whose level may be 50% or less, is an obvious goal. The frequency of such heterozygotes varies from 1:10 to 1:140 or lower depending upon the disease at issue. We assayed the levels of lysosomal enzymes in normal UCB in random samples as well as those used for transplantation. We measured the following enzymatic activities: alpha-l-iduronidase (Hurler), galactocerebrosidase (globoid cell leuko- dystrophy) and arylsulfatase A (metachromatic leukodystrophy). For the latter, levels of activity in UCB are comparable to those found in adult blood. In the case of arylsulfatase B (Maroteaux-Lamy) a level lower than adult level was found. An informed choice by the transplanting physician based on the activity of the relevant enzyme in the UCB donor will provide a better opportunity for an improved prognosis for more complete correction of the recipient's primary disease. Bone Marrow Transplantation (2000) 25, 541-544.

Adult↗
PubMed1997

Retrovirus-mediated transfer of the human alpha-L-iduronidase cDNA into human hematopoietic progenitor cells leads to correction in trans of Hurler fibroblasts.

Hurler syndrome (mucopolysaccharidosis IH or MPS IH) is a congenital mucopolysaccharide storage disorder resulting from a genetic deficiency of alpha-L-iduronidase (IDUA), which is required for lysosomal degradation of glycosaminoglycans heparan sulfate and dermatan sulfate. Even though histocompatible bone marrow transplantation has been applied for the treatment of Hurler syndrome, gene therapy via autologous bone marrow transplantation (BMT) may be more beneficial for this disease. Two retroviral vectors containing a full-length human IDUA cDNA were constructed using Moloney murine leukemia virus (MoMLV)-based vector backbones. High-titer vector-producing clones containing the L-HuID-SN and MFG-HuID retroviral vectors were established. The efficiency of gene transfer into primitive human CD34+ hematopoietic cells using both retroviral vectors is in the range of 18-23%. The level of enzyme expression in transduced primary bone marrow cells was increased 40- to 50-fold compared with that of sham-transduced cells. Enzyme produced by the progeny of the transduced human CD34+ cells carrying IDUA cDNA corrected Hurler fibroblasts via mannose-6-phosphate receptors. These findings suggest that genetically modified hematopoietic progenitor cells can potentially be useful for gene therapy of Hurler syndrome.

Animals↗