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Liver-directed gene therapy of diabetic rats using an HVJ-E vector containing EBV plasmids expressing insulin and GLUT 2 transporter

Gene Therapy volume 13, pages 216–224 (2006)Cite this article

Abstract

Insulin gene therapy in clinical medicine is currently hampered by the inability to regulate insulin secretion in a physiological manner, the inefficiency with which the gene is delivered, and the short duration of gene expression. To address these issues, we injected the liver of streptozotocin-induced diabetic rats with hemagglutinating virus of Japan-envelope (HVJ-E) vectors containing Epstein–Barr virus (EBV) plasmids encoding the genes for insulin and the GLUT 2 transporter. Efficient delivery of the genes was achieved with the HVJ-E vector, and the use of the EBV replicon vector led to prolonged hepatic gene expression. Blood glucose levels were normalized for at least 3 weeks as a result of the gene therapy. Cotransfection of GLUT 2 with insulin permitted the diabetic rats to regulate their blood glucose levels upon exogenous glucose loading in a physiologically appropriate manner and improved postprandial glucose levels. Moreover, cotransfection with insulin and GLUT 2 genes led to in vitro glucose-stimulated insulin secretion that involved the closure of KATP channels. The present study represents a new way to efficiently deliver insulin gene in vivo that is regulated by ambient glucose level with prolonged gene expression. This may provide a basis to overcome limitations of insulin gene therapy in humans.

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Acknowledgements

This work was supported by the Grant No. RTI04-01-01 and RTI04-03-02 from the Regional Technology Innovation Program of the Ministry of Commerce, Industry and Energy (MOCIE). We thank Ishihara Sangyo Kaisha, Ltd (Osaka, Japan) for donating HVJ-E vector.

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Author notes

  1. Y D Kim and K-G Park: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine & Institute for Medical Sciences, Keimyung University School of Medicine, Daegu, South Korea

    Y D Kim, K-G Park, H-S Kim & C-W Nam

  2. Division of Gene Therapy Science, Osaka University Medical School, Osaka, Japan

    R Morishita & Y Kaneda

  3. Department of Physiology, Keimyung University School of Medicine, Daegu, South Korea

    S-Y Kim & D-K Song

  4. Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea

    H C Lee

  5. Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, South Korea

    K-U Lee & J-Y Park

  6. Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea

    B-W Kim, J-G Kim & I-K Lee

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  1. Y D Kim
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Correspondence to I-K Lee.

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Kim, Y., Park, KG., Morishita, R. et al. Liver-directed gene therapy of diabetic rats using an HVJ-E vector containing EBV plasmids expressing insulin and GLUT 2 transporter. Gene Ther 13, 216–224 (2006). https://doi.org/10.1038/sj.gt.3302644

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