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

A Retraction to this article was published on 02 April 2009

Abstract

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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Acknowledgements

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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Lee, H., Kim, SJ., Kim, KS. et al. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 408, 483–488 (2000). https://doi.org/10.1038/35044106

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