Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by deficient beta-glucuronidase (GUSB) activity. Accumulation of glycosaminoglycans (GAGs) in bone, cartilage, and synovium likely contributes to reduced mobility in untreated MPS VII individuals. We previously reported that neonatal intravenous injection of a retroviral vector (RV) expressing canine GUSB resulted in hepatocyte transduction in mice and dogs, and secreted GUSB was taken up from blood by other organs. Here we report the effect of this therapy on bone, cartilage, and joint disease. Osteocytes and bone-lining cells from RV-treated MPS VII mice had GUSB activity, resulting in a marked reduction, as compared with untreated MPS VII mice, in lysosomal storage in bone and at the bone:growth plate interface where bone elongation occurs. Although chondrocytes did not have detectable GUSB activity and had little reduction in lysosomal storage, the thickness of the growth plate was reduced toward normal. These pathological changes were likely responsible for improvements in facial morphology and long bone lengths. The synovium had reduced hyperplasia and lysosomal storage, and the thickness of the articular cartilage was reduced. Similarly, RV-treated MPS VII dogs had improved facial morphology and reduced lysosomal storage in osteocytes and synovium, but not chondrocytes. Nevertheless, the internal area of the trachea was increased, and erosions of the femoral head were reduced. We conclude that neonatal gene therapy can improve bone and joint disease in MPS VII mice and dogs. However, better delivery of GUSB to chondrocytes will be necessary to achieve more profound effects in cartilage.
Mol Genet Metab 2004 May
PMID:Neonatal retroviral vector-mediated hepatic gene therapy reduces bone, joint, and cartilage disease in mucopolysaccharidosis VII mice and dogs. 1511 Mar 16

As a group, lysosomal storage diseases (LSDs) affect roughly 1 in 6700 live births. Treatment of patients with enzyme replacement therapy or allogeneic bone marrow transplantation is severely limited by cost and clinical complications, respectively. In this study, the efficacy of gene therapy targeted to human hematopoietic progenitor cells was investigated for mucopolysaccharidosis type VII (MPSVII), a LSD caused by beta-glucuronidase (GUSB) deficiency. Clinical experience has emphasized the need to evaluate transduction protocols directly with human cells through in vivo assays. Therefore, GUSB-deficient mobilized peripheral blood CD34(+) cells from a patient with MPSVII were transduced with a third-generation lentiviral vector encoding human GUSB and then assessed in a xenotransplantation system. In this novel strategy, the xenotransplanted murine recipients were also GUSB-deficient, allowing a detailed evaluation of therapeutic efficacy in a host with MPSVII. Twelve weeks posttransplantation, lymphomyeloid expression of GUSB was detected in 10.8 +/- 1.6% of the human cells in the bone marrow with an average of 1 to 2 vector genomes measured per positive cell. The corrected cells distributed widely throughout recipient tissues, resulting in significant therapeutic effects including improvements in biochemical parameters and reduction of the lysosomal distension of several host tissues.
Mol Ther 2004 Jun
PMID:Human CD34+ hematopoietic progenitor cell-directed lentiviral-mediated gene therapy in a xenotransplantation model of lysosomal storage disease. 1519 52

CpG-reduced, CMV-based plasmid DNA constructs encoding human alpha-galactosidase A and factor IX were injected into C57Bl/6, BALB/c, and CD1 mice using hydrodynamics-based delivery of plasmid DNA (pDNA), and gene expression was monitored for 6 months. Linearized and supercoiled pDNAs were compared for their abilities to support long-term expression and to generate immune responses to the transgene product. In all mouse strains supercoiled CpG-reduced pDNA encoding alpha-galactosidase A and factor IX generated higher and more sustained levels of circulating gene product than their supercoiled CpG-replete analogs. Linearizing supercoiled CpG-reduced pDNA did not significantly increase levels of circulating gene product beyond levels supercoiled CpG-reduced pDNA could achieve. Linearizing supercoiled CpG-replete pDNA vectors significantly increased expression compared to their supercoiled CpG-replete analogs, but the increase was short-lived or subtherapeutic. Regardless of vector, liver depot expression did not elicit significant antibody responses to human alpha-galactosidase A or factor IX. Taken together, these data suggest that a clinically acceptable hydrodynamics-based approach targeting the liver combined with CpG-reduced pDNA vectors may represent a viable option for individuals with hemophilia, a lysosomal storage disease, or other disease in which prolonged depot expression of a therapeutic protein from the liver is desirable.
Mol Ther 2004 Aug
PMID:Long-term transgene expression from plasmid DNA gene therapy vectors is negatively affected by CpG dinucleotides. 1529 74

Lysosomal storage disorders (LSD) are rare inherited metabolic diseases in which genetic alterations affect lysosomal proteins. Mucopolysaccharidosis type IIIA (MPS-IIIA) is an LSD characterized by reduced activity of sulfamidase (heparan-N-sulfatase, EC3.10.1.1), which degrades the sulfated glycosoaminoglycan heparan sulfate. The central nervous system (CNS) is the main site of pathology in MPS-IIIA, resulting in reduced neurological function and neurocognitive decline. Neuropathological changes include lysosomal vacuolation of heparan sulfate and lipids in neurons, glia, and perivascular cells and the formation of axonal spheroids and ectopic dendrites. At present there is no effective treatment for the CNS effects of LSD as enzyme administered intravenously cannot cross the blood-brain barrier. We have previously established and characterized a mouse model of MPS-IIIA, and in the present study, we injected recombinant human sulfamidase directly into the brain at 6, 12 or 18 weeks of age. Treatment reduced vacuolation and gliosis and delayed the onset of ubiquitin-positive neurodegenerative changes in widespread areas of MPS-IIIA brain, assessed at 24 weeks of age. However, ubiquitin-positive axonal spheroids already detectable by 6 weeks of age were unaffected by treatment at any age, suggesting their irreversibility and thus indicating the importance of early detection of MPS-IIIA and instigation of therapy.
Mol Genet Metab 2004 Aug
PMID:Intracerebral injection of sulfamidase delays neuropathology in murine MPS-IIIA. 1530 25

Mucopolysaccharidosis type VII is a lysosomal storage disease caused by deficiency of the acid hydrolase beta-glucuronidase. MPS VII mice develop progressive lysosomal accumulation of glycosaminoglycans within multiple organs, including the brain. Using this animal model, we investigated whether gene transfer mediated by a recombinant adeno-associated virus (rAAV) type 2 vector is capable of reversing the progression of storage in adult mice. We engineered an rAAV2 vector to carry the murine beta-glucuronidase cDNA under the transcriptional direction of the human elongation factor-1alpha promoter. Intrahepatic administration of this vector in adult MPS VII mice resulted in stable hepatic beta-glucuronidase expression (473 +/- 254% of that found in wild-type mouse liver) for at least 1 year postinjection. There was widespread distribution of vector genomes and beta-glucuronidase within extrahepatic organs. The level of enzyme activity was sufficient to reduce lysosomal storage within the liver, spleen, kidney, heart, lung, and brain. Within selected regions of the brain, neuronal, glial, and perivascular cells had histopathologic evidence of reduced storage. Also, brain alpha-galactosidase and beta-hexosaminidase enzyme levels, secondarily elevated by the storage abnormality, were normalized. These data demonstrate that peripheral administration of an rAAV2 vector in adult MPS VII mice can lead to transgene expression levels sufficient for improvements in both the peripheral and the central manifestations of this disease.
Mol Ther 2004 Sep
PMID:Widespread correction of lysosomal storage following intrahepatic injection of a recombinant adeno-associated virus in the adult MPS VII mouse. 1533 48

Lysosomal storage disorders represent a group of over 45 distinct genetic diseases. The broad spectrum of clinical presentation of this group of disorders has led to the development of diagnostic protocols to facilitate their rapid and accurate diagnosis. However, with the development of new therapies, testing for many of these disorders now extends beyond diagnosis of affected individuals. The efficacy of many current and proposed therapies will rely heavily upon early detection and treatment prior to the onset of irreversible pathology. Newborn screening holds the promise of early detection. However, presymptomatic diagnosis raises a number of issues relating to patient management and treatment. Methods for prognoses and monitoring therapy in asymptomatic individuals will be required.
Expert Rev Mol Diagn 2004 Sep
PMID:Diagnosis of lysosomal storage disorders: current techniques and future directions. 1534 61

Mucopolysaccharidosis IIID (MPS IIID) is a lysosomal storage disease associated with deficient activity of the enzyme N-acetylglucosamine 6-sulfatase (EC 3.1.6.14), a lysosomal hydrolase in the heparan sulfate glycosaminoglycan (HS-GAG) degradation pathway. In caprine MPS IIID, enzyme replacement therapy reversed early postnatal systemic but not primary or secondary central nervous system (CNS) substrate accumulations. The caprine MPS IIID large animal model system was used in this investigation to define the developmental profile of morphological and biochemical perturbations to estimate a time frame for therapeutic intervention. Light and electron microscopy were used to compare the CNS, liver, and kidney of normal +/+, MPS IIID carrier +/-, and MPS IIID-affected -/- goat kids (kids), at 60, 113-114, 128-129, and 135 d gestation (dg) of a 150-d gestational period, at birth, and at 59-64 d of postnatal (d-pn) age. In the CNS of -/- kids, morphological correlations of HS-GAG and glycolipid accumulations were evident in early differentiating neurons at 60 dg. CNS and systemic developmental, regional, and cellular differences in -/- kids at all time points included more prominent and earlier accumulation of lucent, putative HS-GAG substrates in lysosomes of meningeal and perivascular macrophages and hepatic sinusoidal cells than in CNS, hepatic, or renal parenchymal cells. The amounts and compositions of HS-GAG substrates in the brain and liver of +/+, +/-, and -/- kids were determined at 60, 65, 113-114, and 128-135 dg, at birth, and 53-78 d-pn. In the CNS of -/- kids, HS-GAG concentrations were variable and exceeded those of age-matched control tissue samples in the third but not the second trimester. In contrast, hepatic HS-GAG levels in -/- kids exceeded control values at all time points evaluated and paralleled the progressive morphological alterations. CNS and hepatic HS-GAG compositions in -/- kids were similar to each other and were more complex at all pre- and postnatal ages than those from control kids. Based on the time frame of development of CNS lesions and biochemical perturbations, prenatal therapeutic intervention in caprine MPS IIID is likely to be necessary to prevent or ameliorate substantive CNS and systemic lesions.
J Mol Neurosci 2004
PMID:Caprine mucopolysaccharidosis IIID: fetal and neonatal brain and liver glycosaminoglycan and morphological perturbations. 1545 41

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

A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy, which is characterized by accumulation of the sphingolipid 3-O-sulfogalactosylceramide (sulfatide). Sphingolipid storage results in progressive demyelination and severe neurologic symptoms. The disease is lethal, and curative therapy is not available. To assess the therapeutic potential of enzyme replacement therapy (ERT), ASA knockout mice were treated by intravenous injection of recombinant human ASA. Plasma levels of ASA declined with a half-time of approximately 40 min, and enzyme was detectable in tissues within minutes after injection. The uptake of injected enzyme was high into liver, moderate into peripheral nervous system (PNS) and kidney and very low into brain. The apparent half-life of endocytosed enzyme was approximately 4 days. A single injection led to a time- and dose-dependent decline of the excess sulfatide in PNS and kidney by up to 70%, but no reduction was seen in brain. Four weekly injections with 20 mg/kg body weight not only reduced storage in peripheral tissues progressively, but also were surprisingly effective in reducing sulfatide storage in brain and spinal cord. The histopathology of kidney and central nervous system was ameliorated. Improved neuromotor coordination capabilities and normalized peripheral compound motor action potential demonstrate the benefits of ERT on the nervous system function. Enzyme replacement may therefore be a promising therapeutic option in this devastating disease.
Hum Mol Genet 2005 May 01
PMID:Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. 1577 92

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of the enzyme alpha-galactosidase A and results in pain, progressive renal impairment, cardiomyopathy, and cerebrovascular disease. The results of two major randomized, double-blind, placebo-controlled clinical trials and open-label extensions have shown that replacement of the deficient enzyme with either of two preparations of recombinant human alpha-galactosidase A, agalsidase-alfa, and agalsidase-beta is safe. Biweekly i.v. infusions of 0.2 mg/kg of agalsidase-alfa were associated with a significant decrease in pain and stabilization of renal function. Biweekly infusions of 1 mg/kg of agalsidase-beta were associated with virtually complete clearing of accumulated glycolipid substrate from renal and cutaneous capillary endothelial cells. Several smaller, open-label studies, along with observations made in the course of monitoring large numbers of patients on enzyme replacement therapy, indicated that treatment stabilizes renal function and produces significant improvements in myocardial mass and function. Treatment of Fabry disease by enzyme replacement has a significant impact on at least some serious complications of the disease.
Mol Neurobiol 2005 Aug
PMID:Enzyme replacement therapy of Fabry disease. 1607 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>