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Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats

Gene Therapy volume 8, pages 461–468 (2001)Cite this article

Abstract

The anemia associated with chronic renal failure is one of the best target diseases for erythropoietin (Epo) gene transfer. We previously reported a short-term (1 month) study of continuous rat Epo delivery by muscle-targeted gene transfer of plasmid DNA expressing rat Epo (pCAGGS-Epo) using in vivo electroporation in normal rats. Here, we performed a long-term pharmacokinetic study of continuous Epo delivery by this method in normal rats and uremic five-sixths nephrectomized rats. In normal rats, Epo gene expression and sufficient erythropoiesis occurred with Epo gene transfer in a dose-dependent manner, and persisted for at least 11 weeks. Repeated administration of the plasmid DNA effectively produced erythropoiesis. Similar erythropoiesis was observed in the uremic rats, and persisted for more than 15 weeks. Both normal and uremic rats showed a significant decrease in platelet count. Moreover, the uremic rats showed Epo-induced hypertension, which is the major side-effect of recombinant human Epo. These results demonstrate that muscle-targeted pCAGGS-Epo transfer by in vivo electroporation is a useful procedure for the long-term continuous delivery of Epo in both normal and uremic rats.

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Acknowledgements

This work was partly supported by a grant to H Maruyama and M Sugawa from the Renal Anemia Foundation (Tokyo). The authors are grateful to K Yamagiwa of the Department of Medicine II, and Y Maeda and Y Yamamoto of the Institute for Laboratory Animals, Niigata University School of Medicine, for technical assistance.

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Authors and Affiliations

  1. Department of Medicine (II), Niigata University School of Medicine, Niigata, Japan

    H Maruyama, K Ataka, F Gejyo, N Higuchi, Y Ito & H Kikuchi

  2. Department of Surgery (II), Niigata University School of Medicine, Niigata, Japan

    H Hirahara

  3. Product Research Laboratory, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    I Imazeki

  4. Pharmaceutical Research Laboratory, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    M Hirata

  5. Product Planning and Business Development, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    F Ichikawa & T Neichi

  6. Pharmaceutical Technology Laboratory, Chugai Pharmaceutical Co., Ltd., Tokyo, Japan

    M Sugawa

  7. Department of Nutrition and Physiological Chemistry, G6, Osaka University Medical School, Japan

    J Miyazaki

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  1. H Maruyama
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  2. K Ataka
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  11. H Kikuchi
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  12. M Sugawa
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Maruyama, H., Ataka, K., Gejyo, F. et al. Long-term production of erythropoietin after electroporation-mediated transfer of plasmid DNA into the muscles of normal and uremic rats. Gene Ther 8, 461–468 (2001). https://doi.org/10.1038/sj.gt.3301412

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  • DOI: https://doi.org/10.1038/sj.gt.3301412

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