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

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dc.contributor.authorSalvetti, A.
dc.contributor.authorMoullier, P.
dc.contributor.authorCornet, V.
dc.contributor.authorBrooks, D.
dc.contributor.authorHopwood, J.
dc.contributor.authorDanos, O.
dc.contributor.authorHeard, J.M.
dc.date.issued1995
dc.description.abstractMucopolysaccharidose 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 phosphory-lated molecules that could be internalized by naive deficient cells. Neo-organs containing 2 x 107 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. An approach for enzyme replacement in mucopolysaccharidose type I (MPS I) has been examined. Skin fibroblasts were transduced with a retroviral vector containing the human alpha-l-iduronidase cDNA and implanted as neo-organs in nude mice. The presence of the human enzyme in the liver and spleen was detected in treated animals. These data suggest that the implantation of engineered fibroblasts into neo-organs may be of a therapeutic benefit in MPS.
dc.description.statementofresponsibilityAnna Salvetti, Philippe Moullier, Véronique Cornet, Doug Brooks, John J. Hopwood, Olivier Danos, Jean-Michel Heard
dc.identifier.citationHuman Gene Therapy, 1995; 6(9):1153-1159
dc.identifier.doi10.1089/hum.1995.6.9-1153
dc.identifier.issn1043-0342
dc.identifier.issn1557-7422
dc.identifier.orcidBrooks, D. [0000-0001-9098-3626]
dc.identifier.urihttp://hdl.handle.net/2440/7325
dc.language.isoen
dc.publisherMary Ann Liebert
dc.rightsCopyright status unknown
dc.source.urihttps://doi.org/10.1089/hum.1995.6.9-1153
dc.subjectLiver
dc.subjectSpleen
dc.subjectCells, Cultured
dc.subjectFibroblasts
dc.subjectSkin
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectRetroviridae
dc.subjectLysosomal Storage Diseases
dc.subjectIduronidase
dc.subjectDNA, Complementary
dc.subjectCell Transplantation
dc.subjectTransplantation, Autologous
dc.subjectGene Transfer Techniques
dc.subjectTransduction, Genetic
dc.subjectGene Expression
dc.subjectBase Sequence
dc.subjectGenetic Vectors
dc.subjectMolecular Sequence Data
dc.subjectFemale
dc.subjectPromoter Regions, Genetic
dc.titleIn vivo delivery of human α-L-iduronidase in mice implanted with neo-organs
dc.title.alternativeIn vivo delivery of human alpha-L-iduronidase in mice implanted with neo-organs
dc.typeJournal article
pubs.publication-statusPublished

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