Please use this identifier to cite or link to this item: https://doi.org/10.3390/cells9112474
Title: 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
Authors: Sia, K.C.
Fu, Z.Y. 
Calne, R.Y. 
Nathwani, A.C.
Lee, K.O. 
Gan, S.U. 
Keywords: adeno-associated virus serotype 8 (AAV8)
albumin enhancer (3?iALB)
diabetes gene therapy
glucose responsive element (GlRE)
liver-specific glucose-responsive promoter
long-term basal insulin expression
Issue Date: 2020
Publisher: NLM (Medline)
Citation: Sia, 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
Rights: Attribution 4.0 International
Abstract: We 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.
Source Title: Cells
URI: https://scholarbank.nus.edu.sg/handle/10635/199385
ISSN: 20734409
DOI: 10.3390/cells9112474
Rights: Attribution 4.0 International
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