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Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain

Gene Therapy volume 16, pages 1210–1222 (2009)Cite this article

Abstract

We recently described a non-viral gene therapy paradigm offering long-term resolution of established neuropathic pain in several animal models. Here, the requirements for long-term therapeutic effects are described, and evidence is provided for a mechanism of action based on immunological priming of the intrathecal (i.t.) space. Long-term pain reversal was achieved when two i.t. injections of various naked plasmid DNA doses were separated by 5 h to 3 days. We show that an initial DNA injection, regardless of whether a transgene is included, leads to an accumulation of phagocytic innate immune cells. This accumulation coincides with the time in which subsequent DNA injection efficacy is potentiated. We show the ability of non-coding DNA to induce short-term pain reversal that is dependent on endogenous interleukin-10 (IL-10) signaling. Long-term efficacy requires the inclusion of an IL-10F129S transgene in the second injection. Blockade of IL-10, by a neutralizing antibody, either between the two injections or after the second injection induces therapeutic failure. These results show that this gene therapy paradigm uses an initial ‘priming’ injection of DNA to induce accumulation of phagocytic immune cells, allowing for potentiated efficacy of a subsequent ‘therapeutic’ DNA injection in a time- and dose-dependent manner.

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Acknowledgements

Financial support to this work is provided by Avigen and the NIH grants DA018156, DA015642, DA015656 and HL5510.

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Authors and Affiliations

  1. Department of Psychology & Neuroscience, and the Center for Neuroscience University of Colorado, Boulder, CO, USA

    E Sloane, B Jekich, J Mahoney, M Frank, W Seibert, G Huberty, B Coats, J Harrison, S Maier & L R Watkins

  2. Department of Molecular, Cellular, and Developmental Biology University of Colorado, Boulder, CO, USA

    S Langer, T Hughes & L Leinwand

  3. National Cancer Institute, Frederick, MD, USA

    D Klinman

  4. National Institute for Biological Standards and Control, Potters Bar, UK

    S Poole

  5. Avigen Inc, Alameda, CA, USA

    K Johnson & R Chavez

  6. Department of Neurosciences, University of New Mexico—Health Sciences Center, Albuquerque, NM, USA

    E Milligan

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Correspondence to L R Watkins.

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This work was conducted at the University of Colorado, Boulder, CO, USA.

Supplementary Information accompanies the paper on Gene Therapy website (http://www.nature.com/gt)

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Sloane, E., Langer, S., Jekich, B. et al. Immunological priming potentiates non-viral anti-inflammatory gene therapy treatment of neuropathic pain. Gene Ther 16, 1210–1222 (2009). https://doi.org/10.1038/gt.2009.79

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