Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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In this study we have investigated a group of 29 Brazilian patients, who had been diagnosed with the lysosomal storage disorder, Mucopolysaccharidosis type I (MPS-I). MPS I is caused by a deficiency in the lysosomal hydrolase, alpha-L-iduronidase. Ninety percent of the MPS I patients in this study were genotyped and revealed 10 recurrent and thirteen novel IDUA gene mutations. Eight of these new mutations and three common mutations W402X, P533R, and R383H were individually expressed in CHO-K1 cells and analyzed for alpha-L-iduronidase protein and enzyme activity. A correlation was observed between the MPS I patient clinical phenotype and the associated mutant alpha-L-iduronidase protein/enzyme activity expressed in CHO-K1 cells. This was the first time that Brazilian MPS I patients had been thoroughly analyzed and highlighted the difficulties of mutation screening and clinical phenotype assessment in populations with high numbers of unique mutations.
Mol Genet Metab 2003 Jan
PMID:Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients. 1255 46

Mucopolysaccharidosis I is a lysosomal storage disorder caused by mutations in the IDUA gene, resulting in deficiency of alpha-L-iduronidase and accumulation of glycosaminoglycans. Bone marrow transplantation has been the only available therapy, soon to be joined by enzyme replacement. We have tested retroviral gene therapy in a knockout mouse model of the disease. Bone marrow from Idua-/- male donor mice was transduced with human IDUA cDNA in an MND vector and transplanted into 6-8-week-old, lethally irradiated female Idua-/- mice. Sham-treated mice received Idua-/- bone marrow that was either unmodified or transduced with eGFP. Unmodified Idua+/+ (wild type) bone marrow was transplanted for comparison. Recipient mice were sacrificed 2-6 months after transplantation. Three biochemical parameters were used to gauge therapeutic success: appearance of alpha-L-iduronidase activity, reduction of beta-hexosaminidase activity and reduction of soluble glycosaminoglycan accumulation. Transplantation of unmodified +/+ bone marrow was effective in reducing storage in liver and spleen, but not in kidney or brain. The level of alpha-L-iduronidase activity achieved by transplantation of IDUA-transduced bone marrow varied greatly between experiments. But even modest activity resulted in correction of pathology of kidney, bladder epithelium, fibrocartilage, choroid plexus, and thalamus, as seen by light microscopy, while electron microscopy showed the presence of some normal neurons in the cortex. The partial correction of brain pathology is attributed to migration of donor hematopoietic cells, demonstrated by the presence of the Y chromosome and of normal microglia in the brain of mice receiving IDUA cDNA.
Mol Genet Metab 2003 Aug
PMID:Treatment of the mouse model of mucopolysaccharidosis I with retrovirally transduced bone marrow. 1294 39

alpha-L-Iduronidase is a glycosyl hydrolase involved in the sequential degradation of the glycosaminoglycans heparan sulphate and dermatan sulphate. A deficiency in alpha-L-iduronidase results in the lysosomal accumulation and urinary secretion of partially degraded glycosaminoglycans and is the cause of the lysosomal storage disorder mucopolysaccharidosis type I (MPS I; Hurler and Scheie syndromes; McKusick 25280). The premature stop codons Q70X and W402X are two of the most common alpha-l-iduronidase gene (IDUA) mutations accounting for up to 70% of MPS I disease alleles in some populations. Here, we have reported a new mutation, making a total of 15 different mutations that can cause premature IDUA stop codons and have investigated the biochemistry of these mutations. Natural stop codon read-through was dependent on the fidelity of the codon when evaluated at Q70X and W402X in CHO-K1 cells, but the three possible stop codons TAA, TAG and TGA, had different effects on mRNA stability and this effect was context dependent. In CHO-K1 cells expressing the Q70X and W402X mutations, the level of gentamicin-enhanced stop codon read-through was slightly less than the increment in activity caused by a lower fidelity stop codon. In this system, gentamicin had more effect on read-through for the TAA and TGA stop codons when compared to the TAG stop codon. In an MPS I patient study, premature TGA stop codons were associated with a slightly attenuated clinical phenotype, when compared to classical Hurler syndrome (e.g. W402X/W402X and Q70X/Q70X genotypes with TAG stop codons). Natural read-through of premature stop codons is a potential explanation for variable clinical phenotype in MPS I patients. Enhanced stop codon read-through is a potential treatment strategy for a large sub-group of MPS I patients.
J Mol Biol 2004 Apr 30
PMID:alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. 1508 4

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.
Mol Ther 2004 Jun
PMID: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. 1519 53

Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.
Mol Genet Metab
PMID:Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. 1546 31

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.
Mol Ther 2005 Jan
PMID:Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice. 1558 4

Mucopolysaccharidosis I is a lysosomal storage disorder caused by a deficiency of the lysosomal hydrolase alpha-l-iduronidase, which is required for the degradation of heparan sulphate and dermatan sulphate. Given the wide spectrum of disease severity in mucopolysaccharidosis I patients, one of the challenges for managing the disorder is to accurately predict clinical phenotype. Enzyme replacement therapy by intravenous infusion is unlikely to make a significant impact on central nervous system pathology and patients displaying this clinical manifestation may respond better to bone marrow transplantation. In order to predict whether mucopolysaccharidosis I patients are going to develop central nervous system pathology, we investigated a number of biochemical parameters in cultured skin fibroblasts from patients of different genotype/phenotype. Residual levels of alpha-l-iduronidase activity and protein were determined using sensitive immune-quantification assays and fibroblast cell extracts from patients with central nervous system pathology generally had lower levels of alpha-l-iduronidase than patients with no evidence of central nervous system disease. A total of 15 oligosaccharides, derived from heparan sulphate and dermatan sulphate, was measured in fibroblast extracts using electrospray-ionisation tandem mass spectrometry and all were shown to discriminate mucopolysaccharidosis I from controls. Of these, two trisaccharides were able to group patients based on the presence/absence of central nervous system disease. Moreover, a ratio of alpha-l-iduronidase activity to these trisaccharides provided clear discrimination between mucopolysaccharidosis I patients with and without central nervous system pathology. We suggest that this type of analysis may be very useful for predicting disease severity in mucopolysaccharidosis I patients.
Mol Genet Metab 2005 Jan
PMID:Prediction of neuropathology in mucopolysaccharidosis I patients. 1563 91

Mucopolysaccharidosis type I (MPS I) is a lysosomal glycosaminoglycan (GAG) storage disorder caused by deficiency of alpha-l-iduronidase (IDUA). In this study, we evaluated the potential to perform gene therapy for MPS I by direct in vivo injection of a lentiviral vector, using an IDUA gene knockout murine model. We compared the efficacy in newborn versus young adult MPS I mice of a single intravenous injection of the lentiviral vector. The extent of transduction was dose-dependent, with the liver receiving the highest level of vector, but other somatic organs reaching almost the same level. The phenotypic manifestations of disease were partially improved in the mice treated as young adults, but were nearly normalized at every end-point measured in the mice treated as neonates. In the neonatally treated mice, the expressed IDUA activity resulted in decreased GAG storage, prevention of skeletal abnormalities, a more normal gross appearance, and improved survival. Most strikingly, significant levels of IDUA enzyme were produced in the brain of mice treated as neonates, with transduction of neurons at high levels. The sustained expression of enzymatically active IDUA in multiple organs had a significant beneficial effect on the phenotypic abnormalities of MPS I, which may be translated to clinical gene therapy of patients with Hurler disease.
Mol Ther 2005 May
PMID:Neonatal gene therapy of MPS I mice by intravenous injection of a lentiviral vector. 1585 Oct 16

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.
Mol Genet Metab 2005 May
PMID:A homology model for human alpha-l-iduronidase: insights into human disease. 1586 78

Mucopolysaccharidosis I (MPS I, alpha-l-iduronidase deficiency disease) is a heritable lysosomal storage disorder involving multiple organs, including the heart. Malfunction of the heart is also a major manifestation in the mouse model of MPS I, progressing in severity from 6 to 10 months (of a 1 year life span). In comparisons of MPS I with wild-type mice, the heart was found enlarged, with thickened septal and posterior walls, primarily because of infiltration of the muscle by storage-laden cells. Heart valves were enlarged and misshapen, and contained large numbers of highly vacuolated interstitial cells. The thickened aortic wall contained vacuolated smooth muscle cells and interrupted elastic fibers. Hemodynamic measurements and echocardiography revealed reduced left ventricular function as well as mitral and aortic regurgitation. But despite these abnormalities, free-roaming MPS I mice implanted with radio telemetry devices showed surprisingly normal heart rate and blood pressure, though their electrocardiograms were abnormal. An incidental finding of the telemetry studies was a disturbed circadian rhythm in the MPS I mice. Restoration of enzyme activity in the heart of one mouse, by transplantation of retrovirally modified bone marrow, resulted in normalization of left ventricular function as well as loss of storage vacuoles in myocytes and endothelial cells, though not in valvular interstitial cells. This study demonstrates the usefulness of the mouse model for in-depth studies of the cardiovascular component of MPS I.
Mol Genet Metab
PMID:Cardiac manifestations in the mouse model of mucopolysaccharidosis I. 1597 18


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