Correction of murine mucopolysaccharidosis VII by a human beta-glucuronidase transgene.

Kyle, John W.; Birkenmeier, Edward H.; Gwynn, Babette; Vogler, Carole; Hoppe, Peter C.; Hoffmann, Joseph W.; Sly, William S.

doi:10.1073/pnas.87.10.3914

Cited by 63 publications

(26 citation statements)

References 20 publications

(20 reference statements)

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“…The ocular involvement in MPS VII is not responsive to systemic treatment by enzyme therapy, presumably due to the blood-retina barrier (13). Our data show that adenovirusdirected gene transfer to ocular tissues may be useful in this condition, and possibly in other lysosomal storage diseases with ocular phenotypes in conjunction with systemic enzyme or gene therapies.…”

Section: Discussionmentioning

confidence: 82%

“…Cells that are deficient in 13-glucuronidase because of gene mutations are still able to endocytose the normal enzyme from external medium when available and correct their disease phenotype (10). Thus bone marrow transplantation or tissue grafting with normal cells or genetically modified cells in adult animals corrects the lysosomal storage in most organs (6,(11)(12)(13)(14)(15). However, signs of disease remain in the CNS and in the retina.…”

mentioning

confidence: 99%

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Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VII by adenovirus-mediated gene transfer.

Davidson

1995

Proc. Natl. Acad. Sci. U.S.A.

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We have studied the use of adenovirusmediated gene transfer to reverse the pathologic changes of lysosomal storage disease caused by j8-glucuronidase deficiency in the eyes of mice with mucopolysaccharidosis VII. A recombinant adenovirus carrying the human 18-glucuronidase cDNA coding region under the control of a non-tissue-specific promoter was injected intravitreally or subretinally into the eyes of mice with mucopolysaccharidosis VII. At 1-3 weeks after injection, the treated and control eyes were examined histochemically for j3-glucuronidase expression and histologically for phenotypic correction of the lysosomal storage defect. Enzymatic expression was detected 1-3 weeks after injection. Storage vacuoles in the retinal pigment epithelium (RPE) were still present 1 week after gene transfer but were reduced to undetectable levels by 3 weeks in both intravitreally and subretinally injected eyes. There was minimal evidence of ocular pathology associated with the viral injection. These data indicate that adenovirus-mediated gene transfer to the eye may provide for adjunctive therapy for lysosomal storage diseases affecting the RPE in conjunction with enzyme replacement and/or gene therapies for correction of systemic disease manifestations. The data also support the view that recombinant adenovirus may be useful as a gene therapy vector for retinal degenerations that result from a primary genetic defect in the RPE cells.The mucopolysaccharidoses (MPSs) represent a broad spectrum of inherited metabolic diseases caused by deficiencies in one of several enzymes responsible for the degradation of mucopolysaccharides. The MPS syndromes show progressive clinical involvement and are characterized by coarse faces, dysostosis multiplex, joint abnormalities, and various degrees of central nervous system (CNS) abnormalities. Depending on the particular types of MPS, ocular features may include corneal clouding, retinal degeneration, optic atrophy, and glaucoma. These phenotypic abnormalities are a result of lysosomal accumulation of glycosaminoglycans that eventually leads to cell and organ dysfunction.Genetic mutations that cause a severe reduction in the level of 0-glucuronidase (13-D-glucuronoside glucuronosohydrolase, EC 3.2

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VII by adenovirus-mediated gene transfer.

Davidson

1995

Proc. Natl. Acad. Sci. U.S.A.

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“…This expression cassette was chosen since it was known to mediate highlevel expression in a wide variety of cell types. These characteristics were desirable for this application since overexpression of GUSB does not appear to be toxic, 24 overexpressing cells secrete proportionally higher amounts of enzyme 25 and GUSB is normally expressed in virtually every cell of the body. Based on previous studies using ERT and BMT, it seems likely that the primary mechanism for improvements in weight, bone length, and dysmorphic features seen in this study are the high levels of GUSB produced during the first month of life.…”

Section: Figure 7 Neonatal Aav Treatment Results In Prolonged Longevimentioning

confidence: 99%

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

et al. 2001

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“…The MPS VII͞E540A Tg mice showed the profound deficiency of ␤-glucuronidase characteristic of MPS VII (gus mps/mps ) mice (6). They also showed the secondary elevations in tissue levels of ␣-galactosidase (10,48). This secondary elevation has been shown to be a convenient measure of lysosomal storage secondary to ␤-glucuronidase deficiency and provided a means to follow the biochemical response to therapy.…”

Section: Mutant Phenotype Of the Hgus͞e540a Transgenic Mps VII Micementioning

confidence: 99%

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

Sly

Vogler

Grubb

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is an autosomal recessive lysosomal storage disorder due to an inherited deficiency of ␤-glucuronidase. A naturally occurring mouse model for this disease was discovered at The Jackson Laboratory and shown to be due to homozygosity for a 1-bp deletion in exon 10 of the gus gene. The murine model MPS VII (gus mps/mps ) has been very well characterized and used extensively to evaluate experimental strategies for lysosomal storage diseases, including bone marrow transplantation, enzyme replacement therapy, and gene therapy. To enhance the value of this model for enzyme and gene therapy, we produced a transgenic mouse expressing the human ␤-glucuronidase cDNA with an amino acid substitution at the active site nucleophile (E540A) and bred it onto the MPS VII (gus mps/mps ) background. We demonstrate here that the mutant mice bearing the active site mutant human transgene retain the clinical, morphological, biochemical, and histopathological characteristics of the original MPS VII (gus mps/mps ) mouse. However, they are now tolerant to immune challenge with human ␤-glucuronidase. This ''tolerant MPS VII mouse model'' should be useful for preclinical trials evaluating the effectiveness of enzyme and͞or gene therapy with the human gene products likely to be administered to human patients with MPS VII.

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Correction of murine mucopolysaccharidosis VII by a human beta-glucuronidase transgene.

Cited by 63 publications

References 20 publications

Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VII by adenovirus-mediated gene transfer.

Phenotype correction in retinal pigment epithelium in murine mucopolysaccharidosis VII by adenovirus-mediated gene transfer.

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

Active site mutant transgene confers tolerance to human β-glucuronidase without affecting the phenotype of MPS VII mice

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