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dc.contributor.authorRen, B.en_US
dc.contributor.authorO⿿Brien, B.en_US
dc.contributor.authorSwan, M.en_US
dc.contributor.authorKoina, M.en_US
dc.contributor.authorNassif, N.en_US
dc.contributor.authorWei, M.en_US
dc.contributor.authorSimpson, M.en_US
dc.date.accessioned2017-05-03T15:52:25Z
dc.date.available2017-05-03T15:52:25Z
dc.date.issued2007en_US
dc.date.modified2010-08-13T07:23:18Z
dc.identifier.issn0012186Xen_US
dc.identifier.doi10.1007/s00125-007-0722-0en_AU
dc.identifier.urihttp://hdl.handle.net/10072/33004
dc.description.abstractAIMS/HYPOTHESIS: Type 1 diabetes results from the autoimmune destruction of pancreatic beta cells. Exogenous insulin therapy cannot achieve precise physiological control of blood glucose concentrations, and debilitating complications develop. Lentiviral vectors are promising tools for liver-directed gene therapy. However, to date, transduction rates in vivo remain low in hepatocytes, without the induction of cell cycling. We investigated long-term transgene expression in quiescent hepatocytes in vitro and determined whether the lentiviral delivery of furin-cleavable insulin to the liver could reverse diabetes in rats. MATERIALS AND METHODS: To improve transduction efficiency in vitro, we optimised hepatocyte isolation and maintenance protocols and, using an improved surgical delivery method, delivered furin-cleavable insulin alone or empty vector to the livers of streptozotocin-induced diabetic rats by means of a lentiviral vector. Rats were monitored for changes in body weight and blood glucose, and intravenous glucose tolerance tests were performed. Expression of insulin was determined by RT-PCR, immunohistochemistry and electron microscopy. RESULTS: We achieved long-term transgene expression in quiescent hepatocytes in vitro (87 +/- 1.2% transduction efficiency), with up to 60 +/- 3.2% transduction in vivo. We normalised blood glucose for 500 days-a significantly longer period than previously reported-making this the first successful study using a lentiviral vector. This procedure resulted in the expression of genes encoding several beta cell transcription factors, some pancreatic endocrine transdifferentiation, hepatic insulin storage in granules, and restoration of glucose tolerance. Liver function tests remained normal. Importantly, pancreatic exocrine transdifferentiation did not occur. CONCLUSIONS/INTERPRETATION: Our data suggest that this regimen may ultimately be employed for the treatment of type 1 diabetes.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherSpringeren_US
dc.publisher.placeGermanyen_US
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom1910en_US
dc.relation.ispartofpageto1920en_US
dc.relation.ispartofissue9en_US
dc.relation.ispartofjournalDiabetologiaen_US
dc.relation.ispartofvolume50en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchClinical Sciences not elsewhere classifieden_US
dc.subject.fieldofresearchcode110399en_US
dc.titleLong-term correction of diabetes in rats after lentiviral hepatic insulin gene therapyen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.date.issued2007
gro.hasfulltextNo Full Text


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