Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue

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  • This article was retracted on 02 April 2009


A cure for diabetes has long been sought using several different approaches, including islet transplantation, regeneration of β cells and insulin gene therapy1. However, permanent remission of type 1 diabetes has not yet been satisfactorily achieved. The development of type 1 diabetes results from the almost total destruction of insulin-producing pancreatic β cells by autoimmune responses specific to β cells2,3,4,5,6. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells7. We used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. Here we show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side effects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.

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Figure 1: Construction of pLPK-SIA, hypoglycaemic effect of pLPK-SIA and hepatocyte-specific expression of pLPK-SIA.
Figure 2: Hypoglycaemic effect of rAAV-LPK-SIA and integration of rAAV-LPK-SIA DNA into hepatocyte DNA.
Figure 3: Expression of SIA in hepatocytes and plasma of rAAV-LPK-SIA-treated rats.
Figure 4: Response of SIA to glucose in rAAV-LPK-SIA-treated STZ-induced diabetic rats.
Figure 5: Remission of autoimmune diabetes in NOD mice by administration of rAAV-LPK-SIA.


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We thank R. J. Samulski for providing psub201 and pXX2, A. L. Kyle and K. Clarke for editorial assistance and B. Pinder for artwork. We also thank H. S. Jun for a critical review of the manuscript. J. W. Y. is a Heritage Medical Scientist awardee of the Alberta Heritage Foundation for Medical Research. This work was supported in part by Brain Korea 21 Project.

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Correspondence to Hyun Chul Lee.

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