Abstract
Genetic defects of lysosomal hydrolases result in severe storage diseases and treatments based on enzyme replacement have been proposed. In mice lacking beta-glucuronidase, which develop a disease homologous to human mucopolysaccharidosis type VII (Sly syndrome), we have used autologous implants of genetically-modified skin fibroblasts for the continuous in vivo production of the enzyme. The human beta-glucuronidase cDNA was introduced with a retroviral vector into mutant mice skin fibroblasts grown in primary culture. Fourteen mutant mice were implanted intraperitoneally with these modified cells embedded into collagen lattices. All animals expressed beta-glucuronidase from the vascularized neo-organs that developed after implantation and accumulated the enzyme in their tissues. A complete disappearance of the lysosomal storage lesions was observed in their liver and spleen.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Disease Models, Animal*
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Fibroblasts / enzymology
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Fibroblasts / transplantation*
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Genetic Therapy / methods*
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Genetic Vectors
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Glucuronidase / administration & dosage
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Glucuronidase / deficiency*
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Glucuronidase / genetics
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Glucuronidase / therapeutic use
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Glycosaminoglycans / metabolism
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Liver / enzymology*
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Liver / pathology
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Lysosomes / enzymology*
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Mice
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Mice, Mutant Strains / genetics*
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Mucopolysaccharidosis VII / enzymology
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Mucopolysaccharidosis VII / genetics
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Mucopolysaccharidosis VII / pathology
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Mucopolysaccharidosis VII / therapy*
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Organ Specificity
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Peritoneal Cavity
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Phenotype
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Prostheses and Implants*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / therapeutic use*
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Retroviridae / genetics
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Spleen / enzymology*
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Spleen / pathology
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Transfection
Substances
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Glycosaminoglycans
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Recombinant Fusion Proteins
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Glucuronidase