Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice

Authors

  • Julien Crettaz,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Pedro Berraondo,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
    Current affiliation:
    1. Unité de Biologie des Régulations Immunitaires, INSERM E 352, Institut Pasteur, Paris, France
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  • Itsaso Mauleón,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Laura Ochoa,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Vijay Shankar,

    1. Division of Gene Therapy, University of Ulm, Ulm, Germany
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  • Miguel Barajas,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
    Current affiliation:
    1. Division of Hematology, Department of Medicine, University of Minnesota, Minneapolis, MN
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  • Nico van Rooijen,

    1. Department of Cell and Immunology, Faculty of Medicine, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
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  • Stefan Kochanek,

    1. Division of Gene Therapy, University of Ulm, Ulm, Germany
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  • Cheng Qian,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Jesús Prieto,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Rubén Hernández-Alcoceba,

    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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  • Gloria González-Aseguinolaza

    Corresponding author
    1. Division of Gene Therapy and Hepatology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
    • Centro de Investigación Médica Aplicada (CIMA), Terapia Génica de Hepatitis Virales, Avda Pío XII 55, 31008 Pamplona, Spain
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    • fax: (34) 94 81 94 717

Errata

This article is corrected by:

  1. Errata: Corrections: Intrahepatic injection of adenovirus reduces inflammation and increases gene transfer and therapeutic effect in mice Volume 54, Issue 6, 2280, Article first published online: 30 November 2011

  • Potential conflict of interest: Nothing to report.

Abstract

Recombinant adenoviruses (Ad) are among the most extensively used vectors for liver gene transfer. One of the major limitations for the clinical application of these vectors is the inflammatory immune response associated with systemic administration of high dose of virus. We evaluated the effect of Ad administration route on the inflammatory immune response and liver transgene expression. We compared direct intrahepatic injection (IH) with the systemic administration via tail vein (IV). IH injection of Ad resulted in a lower inflammatory response and a higher transgene expression. When a relatively low dose of virus was used, IV administration resulted in no detectable protein expression but production of proinflammatory cytokines. In contrast, IH administration induced high levels of transgene expression and no inflammation, although we detected a transient hypertransaminemia, which fully resolved within days. Furthermore, IH injection resulted in a faster protein expression being more intense at the site of injection, whereas IV administration caused slower but diffuse liver expression. IH injection also reduced the spreading of the virus to other organs. Independently of the route, depletion of Kupffer cells significantly enhanced the transduction efficiency of Ad. This effect was stronger when using IV injection, indicating that IH injection partially overcomes Kupffer cell phagocytic activity. Moreover, the antitumor efficacy of high-capacity-Ad encoding murine interleukin-12 (IL-12) was significantly greater when the vector was administered by IH injection than when given IV. In conclusion, IH injection of adenovirus represents a safe and efficient administration route for clinical applications of gene therapy targeting the liver. (HEPATOLOGY 2006.)

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