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In vivo delivery of human alpha-L-iduronidase in mice implanted with neo-organs.

Salvetti, A; Moullier, P; Cornet, V; Brooks, D; Hopwood, JJ; Danos, O; Heard, JM; (1995) In vivo delivery of human alpha-L-iduronidase in mice implanted with neo-organs. Hum Gene Ther , 6 (9) pp. 1153-1159. 10.1089/hum.1995.6.9-1153.

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Abstract

Mucopolysaccharidose type I is a lysosomal storage disease caused by a deficiency in the enzyme alpha-L-iduronidase (IDUA). The existence of a secretory pathway for lysosomal enzymes and the capture of secreted molecules by distant cells through binding to mannose-6-phosphate receptors have provided a rationale for enzyme replacement therapy in lysosomal storage diseases. We have used genetically modified fibroblasts implanted into neo-organs as an in vivo delivery system for IDUA. The human IDUA cDNA was isolated and inserted into a retroviral vector where it was expressed from the phosphoglycerate kinase 1 gene promoter. MPS I fibroblasts transduced with this vector showed high levels of IDUA activity and secreted phosphorylated molecules that could be internalized by naive deficient cells. Neo-organs containing 2 x 10(7) IDUA-secreting cells were implanted into nude mice. Human and murine IDUA activities were measured in the liver and spleen of animals sacrificed 35-77 days after implantation. Human IDUA activity corresponded to 0.6-2.3% of the murine enzyme activity in the liver and to 0.1-0.3% in the spleen. These data indicated that human IDUA was secreted from neo-organs and internalized in distant tissues.

Type: Article
Title: In vivo delivery of human alpha-L-iduronidase in mice implanted with neo-organs.
Location: United States
DOI: 10.1089/hum.1995.6.9-1153
Keywords: Animals, Base Sequence, Cell Transplantation, Cells, Cultured, DNA, Complementary, Female, Fibroblasts, Gene Expression, Gene Transfer Techniques, Genetic Vectors, Humans, Iduronidase, Liver, Lysosomal Storage Diseases, Mice, Mice, Nude, Molecular Sequence Data, Promoter Regions, Genetic, Retroviridae, Skin, Spleen, Transduction, Genetic, Transplantation, Autologous
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/90908
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