Please use this identifier to cite or link to this item: https://doi.org/10.3390/cells9112474
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dc.titleModification of a Constitutive to Glucose-Responsive Liver-Specific Promoter Resulted in Increased Efficacy of Adeno-Associated Virus Serotype 8-Insulin Gene Therapy of Diabetic Mice
dc.contributor.authorSia, K.C.
dc.contributor.authorFu, Z.Y.
dc.contributor.authorCalne, R.Y.
dc.contributor.authorNathwani, A.C.
dc.contributor.authorLee, K.O.
dc.contributor.authorGan, S.U.
dc.date.accessioned2021-08-25T14:16:31Z
dc.date.available2021-08-25T14:16:31Z
dc.date.issued2020
dc.identifier.citationSia, K.C., Fu, Z.Y., Calne, R.Y., Nathwani, A.C., Lee, K.O., Gan, S.U. (2020). Modification of a Constitutive to Glucose-Responsive Liver-Specific Promoter Resulted in Increased Efficacy of Adeno-Associated Virus Serotype 8-Insulin Gene Therapy of Diabetic Mice. Cells 9 (11). ScholarBank@NUS Repository. https://doi.org/10.3390/cells9112474
dc.identifier.issn20734409
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/199385
dc.description.abstractWe have previously used a hepatotropic adeno-associated viral (AAV) vector with a modified human insulin gene to treat diabetic mice. The HLP (hybrid liver-specific promoter) used was constitutively active and non-responsive to glucose. In this study, we examined the effects of addition of glucose responsive elements (R3G) and incorporation of a 3' albumin enhancer (3'iALB) on insulin expression. In comparison with the original promoter, glucose responsiveness was only observed in the modified promoters in vitro with a 36 h lag time before the peak expression. A 50% decrease in the number of viral particles at 5 × 109 vector genome (vg)/mouse was required by AAV8-R3GHLP-hINSco to reduce the blood sugar level to near normoglycemia when compared to the original AAV8-HLP-hINSco that needed 1 × 1010 vg/mouse. The further inclusion of an 860 base-pairs 3'iALB enhancer component in the 3' untranslated region increased the in vitro gene expression significantly but this increase was not observed when the packaged virus was systemically injected in vivo. The addition of R3G to the HLP promoter in the AAV8-human insulin vector increased the insulin expression and secretion, thereby lowering the required dosage for basal insulin treatment. This in turn reduces the risk of liver toxicity and cost of vector production.
dc.publisherNLM (Medline)
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceScopus OA2020
dc.subjectadeno-associated virus serotype 8 (AAV8)
dc.subjectalbumin enhancer (3?iALB)
dc.subjectdiabetes gene therapy
dc.subjectglucose responsive element (GlRE)
dc.subjectliver-specific glucose-responsive promoter
dc.subjectlong-term basal insulin expression
dc.typeArticle
dc.contributor.departmentDEPT OF SURGERY
dc.contributor.departmentDEPT OF MEDICINE
dc.description.doi10.3390/cells9112474
dc.description.sourcetitleCells
dc.description.volume9
dc.description.issue11
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