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

Cell-mediated gene therapy for visceral lesions of lysosomal storage diseases is promising; however, the treatment of central nervous system (CNS) lesions remains a challenge. In this study, we generated rat amniotic epithelial cells (AEC) that overexpress and secrete human beta-glucuronidase (GUSB) following transduction with an adenoviral vector encoding human GUSB. The AEC were used as donor cells for cell-mediated gene therapy of CNS lesions in mice with mucopolysaccharidosis type VII (MPSVII), a lysosomal storage disorder caused by an inherited deficiency of GUSB activity. After confirmation that the secreted GUSB was taken up mainly via mannose 6-phosphate receptors in primary cultured neurons, the AEC were transplanted into the brains of adult MPSVII mice. Histochemical analysis showed extensive GUSB activity throughout the ipsilateral hemisphere of the recipient brains, and pathological improvement of the lysosomal storage was observed even in regions far from the site of injection. These results suggest that intracerebral transplantation of genetically engineered AEC has therapeutic potential for the treatment of CNS lesions in lysosomal storage disorders.
Mol Ther 2001 Feb
PMID:Engraftment of genetically engineered amniotic epithelial cells corrects lysosomal storage in multiple areas of the brain in mucopolysaccharidosis type VII mice. 1123 70

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the lack of beta-glucuronidase (GUSB) activity. GUSB deficiency leads to the progressive accumulation of undegraded glycosaminoglycans (GAGs) in cells of most tissues, including the brain, and is associated with mental retardation. Reduction of lysosomal storage in the central nervous system and prevention of cognitive dysfunction may require intracranial delivery of a therapeutic agent during the newborn period that provides a continuous source of GUSB. Therefore, we injected recombinant adeno-associated virus encoding human GUSB into both the anterior cortex and the hippocampus of newborn MPS VII mice. Total GUSB activity in the brain approached normal levels by 18 weeks. Although GUSB activity was concentrated near the injection sites, lysosomal distension was reduced in most areas of the brain. In addition to histopathologic evidence of GAG reduction, the previously undescribed accumulation of GM2 and GM3 gangliosides in the brain was also prevented. Furthermore, GUSB expression and reduced lysosomal distension correlated with improvements in cognitive function as measured in the Morris Water Maze test. These findings indicate that localized overexpression of GUSB has positive effects on the pathology and cognitive function and does not have overt toxicity.
Mol Ther 2001 Mar
PMID:Intracranial injection of recombinant adeno-associated virus improves cognitive function in a murine model of mucopolysaccharidosis type VII. 1127 77

Gene therapy holds great promise for the treatment of a variety of inherited diseases, including hemophilia A and mucopolysaccharidosis type VII (MPS VII). In both these disorders, subnormal levels of replacement protein have therapeutic effects. Thus we hypothesized that transduction of a small proportion of cells by feline immunodeficiency virus (FIV)-based lentiviral vectors might provide sufficient levels of transgene expression for phenotypic correction. We intravenously injected replication-deficient FIV-based vectors encoding either human factor VIII or human beta-glucuronidase into factor VIII-deficient or beta-glucuronidase-deficient mice, respectively. This route of delivery targeted multiple organs, with the liver as the primary transduction site. In the hemophilia A mice, factor VIII expression persisted for the duration of the experiments (approximately 5 months), and recipient mice survived an otherwise lethal bleeding episode (tail-clipping). In mucopolysaccharidosis type VII mice, substantial beta-glucuronidase activity was detected in several tissues and corresponded with marked reduction of lysosomal storage in liver and spleen. These findings indicate that gene transfer with FIV-based lentiviral vectors can permanently introduce transgenes into a sufficient number of hepatocytes for long-term therapeutic effect and suggest potential clinical value of FIV-based lentiviral vectors for treatment of hemophilia A and MPS VII.
Mol Ther 2001 Jun
PMID:In vivo treatment of hemophilia A and mucopolysaccharidosis type VII using nonprimate lentiviral vectors. 1140 98

Recent advances in systemic treatments for mucopolysaccharidosis have led to therapies that improve the multiple somatic features of this disease, but the therapeutic effect on ocular manifestations such as corneal clouding is not satisfactory. Here, we administered an adenovirus expressing human beta-glucuronidase (AxCAhGUS) into the anterior chamber or intrastromal region of the cornea in mice with mucopolysaccharidosis type VII (B6/MPSVII), and successfully treated corneal clouding of MPSVII. When we injected AxCAhGUS into the anterior chamber of the eyes, cells expressing beta-glucuronidase (GUSB) were located mainly in the trabecular meshwork as well as in all corneal regions, and subsequent pathological corrections in the cornea were achieved. Widespread transgene expression was also observed when we administered AxCAhGUS inside the cornea after lamellar keratotomy, and rapid elimination of the lysosomal storage in the corneal keratocytes occurred. Furthermore, intrastromal vector administration did not generate significant levels of anti-adenovirus neutralizing antibodies, and secondary vector administration was effective. Based on these observations, we conclude that it is worth developing a treatment strategy for corneal clouding in mucopolysaccharidosis based on direct intraocular administration of adenoviral vectors.
Mol Ther 2001 Oct
PMID:Adenovirus-mediated gene therapy for corneal clouding in mice with mucopolysaccharidosis type VII. 1159 32

Lysosomal storage diseases, such as Mucopolysaccharidosis type VII (MPS VII), cause progressive loss of mobility and intellect and result in early death. Treatment of progressive diseases must occur before the blood-brain barrier closes. In MPS VII mice, normal donor hematopoietic cells secrete the missing enzyme beta-glucuronidase (GUSB) that reverses disease manifestations. Correction of lysosomal storage is limited to the visceral organs unless transplantation is preceded by high-dose irradiation. We hypothesize that irradiation opens the blood-brain barrier allowing passage of corrective cells. Here we transplanted genetically myeloablated MPS VII fetuses to determine whether earlier treatment without toxic irradiation is systemically corrective. Cells with a selective advantage in utero were identified. Donor fetal liver cells (FLC), a substitute for difficult to obtain murine cord blood cells, were increased 10-fold in the host peripheral blood over equivalent numbers of adult marrow cells injected simultaneously and were stable long term in both primary and secondary hosts. GUSB- MPS VII fetuses injected with GUSB+ FLC were assessed longitudinally after birth. Donor FLC replaced host stem cell descendants, prolonged life dramatically, and reduced bone dysplasia and lysosomal storage in all tissues long term. GUSB, donor leptomeningeal cells, and microglia were present in the brain at 11 months postinjection. Lysosomal storage in cortical neurons and glia, although not completely corrected, was reduced. We conclude that in utero intervention without toxic pretreatment in this model reduces the storage disease long term and improves the length and quality of life despite exerting only minor effects on the brain.
Blood Cells Mol Dis
PMID:In utero fetal liver cell transplantation without toxic irradiation alleviates lysosomal storage in mice with mucopolysaccharidosis type VII. 1178 49

The use of Moloney murine leukemia virus (MLV)-based retroviral vectors (RV) can result in stable in vivo expression in the liver, but these vectors only transduce replicating hepatocytes. As newborn animals exhibit rapid growth, we evaluated the ability of MLV-based RV to transduce hepatocytes in neonatal dogs. I.v. injection of a beta-galactosidase-expressing RV at 3 days after birth resulted in transduction of 9% of hepatocytes. Prior treatment with human hepatocyte growth factor at 2.5 mg/kg did not increase transduction. Although cells from the spleen were also transduced with moderate efficiency, cells from other organs were not. Neonatal dogs with mucopolysaccharidosis VII (MPS VII) received an i.v.injection of an RV containing the canine beta-glucuronidase (cGUSB) cDNA. At several months after transduction, clusters of hepatocytes that expressed high levels of cGUSB were present in the liver, which probably derived from replication of transduced hepatocytes. At 6 months after transduction, serum GUSB levels were 73% that of homozygous normal dogs and were 34% of the peak values observed at 1 week. We conclude that neonatal delivery of an MLV-based RV results in stable transduction of hepatocytes in dogs. This approach could result in immediate correction in patients with an otherwise-lethal genetic deficiency.
Mol Ther 2002 Feb
PMID:Transduction of hepatocytes after neonatal delivery of a Moloney murine leukemia virus based retroviral vector results in long-term expression of beta-glucuronidase in mucopolysaccharidosis VII dogs. 1182 21

Mucopolysaccharidosis type VII (MPS VII) is an inherited disease caused by beta-glucuronidase (beta-glu) deficiency. This deficiency results in the lysosomal accumulation of glycosaminoglycans in all tissues and affects a wide range of organs, including the central nervous system (CNS). Gene transfer is a promising approach to therapy for MPS VII because it allows extensive delivery of the enzyme to the affected tissues. We studied neurotransplantation of primary human cells to supply beta-glucuronidase to the CNS. Human neural progenitor cells (HNPC) were amplified and cotransduced with two lentiviral vectors, one encoding the green fluorescent protein and the other the human beta-glu. We show that these cells strongly expressed both transgenes in culture. When grafted into the mouse striatum, HNPC differentiated into neurons and astrocytes and expressed the two transgenes for at least 6 months. This study therefore paves the way for the treatment of MPS VII by long-term delivery of the appropriate enzyme.
Mol Cell Neurosci 2002 Mar
PMID:Long-term expression of beta-glucuronidase by genetically modified human neural progenitor cells grafted into the mouse central nervous system. 1190 11

Previous treatment of mucopolysaccharidosis type VII mice (Sly syndrome) with AAV vectors has resulted in increased levels of beta-glucuronidase (GUS) enzyme in some tissues with reduction of glycosaminoglycan storage granules and improved health. By adding coding sequences for secretion (Igkappa) and uptake (HIV-1 TAT) signals to the GUS gene delivered by AAV, and treating mice both intrathecally and intravenously as newborns, we have increased the GUS enzyme levels in more tissues and have improved the health of the mice so much that they are able to breed. The levels of GUS in the serum were above normal in some mice, which caused reduction of storage in the spleen, a nontransduced tissue. The heart and aorta showed therapeutic levels of GUS enzyme. AAV GUS DNA was found in brain and liver, which showed no storage. Phenotypically the treated mice were more active and showed less stunted skeletal growth. The pups born to these mice were not affected by the gene therapy, as shown by mutant levels of GUS enzyme in their tissues and the absence of AAV GUS DNA. However, they were resistant to intravenous treatment with AAV GUS due to the mother's antibodies, but not to intrathecal treatment.
Mol Ther 2002 May
PMID:Enhanced secretion and uptake of beta-glucuronidase improves adeno-associated viral-mediated gene therapy of mucopolysaccharidosis type VII mice. 1199 53

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. Intravenous injection of a retroviral vector expressing canine GUSB into neonatal MPS VII mice resulted in transduction of 6 to 35% of hepatocytes, which secreted GUSB into blood. Serum GUSB activity was stable for 6 months at 600 (low expression) to 10,000 (high expression) U/ml, and enzyme was modified appropriately with mannose 6-phosphate. The average serum GUSB activity (3531 U/ml) is the highest long-term expression reported for MPS VII mice after gene therapy. Secreted enzyme was taken up by other tissues, as the average enzyme activity was >13% of normal in somatic organs and 2% of normal in brain. Low expression markedly reduced histopathological evidence of lysosomal storage in liver, spleen, kidney, small intestine, neurons, and glial cells. High expression appeared to be more effective than low expression at reducing lysosomal storage in aorta, heart valves, thymus, bronchial epithelium, cornea, and retinal pigmented epithelium. Future experiments will determine if greater pathological improvements will consistently be observed in retrovirus-treated MPS VII mice with higher serum GUSB activity relative to animals with lower activity and if these result in clinical benefits.
Mol Ther 2002 Dec
PMID:Evaluation of pathological manifestations of disease in mucopolysaccharidosis VII mice after neonatal hepatic gene therapy. 1249 71

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an autosomal recessive lysosomal storage disease caused by beta-glucuronidase (GUS) deficiency. A naturally occurring mouse model of that disease has been very useful for studying experimental approaches to therapy. However, immune responses can complicate evaluation of the long-term benefits of enzyme replacement or gene therapy delivered to adult MPS VII mice. To make this model useful for studying the long-term effectiveness and side effects of experimental therapies delivered to adult mice, we developed a new MPS VII mouse model, which is tolerant to both human and murine GUS. To achieve this, we used homologous recombination to introduce simultaneously a human cDNA transgene expressing inactive human GUS into intron 9 of the murine Gus gene and a targeted active site mutation (E536A) into the adjacent exon 10. When the heterozygote products of germline transmission were bred to homozygosity, the homozygous mice expressed no GUS enzyme activity but expressed inactive human GUS protein highly and were tolerant to immune challenge with human enzyme. Expression of the mutant murine Gus gene was reduced to about 10% of normal levels, but the inactive murine GUS enzyme also conferred tolerance to murine GUS. This MPS VII mouse model should be useful to evaluate therapeutic responses in adult mice receiving repetitive doses of enzyme or mice receiving gene therapy as adults. Heterozygotes expressed only 9.5-26% of wild-type levels of murine GUS instead of the expected 50%, indicating a dominant-negative effect of the mutant enzyme monomers on the activity of GUS tetramers in different tissues. Corrective gene therapy in this model should provide high enough levels of expression of normal GUS monomers to overcome the dominant negative effect of mutant monomers on newly synthesized GUS tetramers in most tissues.
Hum Mol Genet 2003 May 01
PMID:Production of MPS VII mouse (Gus(tm(hE540A x mE536A)Sly)) doubly tolerant to human and mouse beta-glucuronidase. 1270 Jan 65


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