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Intrathecal polymer-based interleukin-10* gene delivery for neuropathic pain

Published online by Cambridge University Press:  13 July 2007

Erin D. Milligan ,
Ryan G. Soderquist ,
Stephanie M. Malone ,
John H. Mahoney ,
Travis S. Hughes ,
Stephen J. Langer ,
Evan M. Sloane ,
Steven F. Maier ,
Leslie A. Leinwand  and
Linda R. Watkins
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Erin D. Milligan*
Affiliation:
Department of Psychology and the Center for Neuroscience, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Ryan G. Soderquist
Affiliation:
Department of Chemical and Biological Engineering, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Stephanie M. Malone
Affiliation:
Department of Molecular, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
John H. Mahoney
Affiliation:
Department of Psychology and the Center for Neuroscience, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Travis S. Hughes
Affiliation:
Department of Molecular, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Stephen J. Langer
Affiliation:
Department of Molecular, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Evan M. Sloane
Affiliation:
Department of Psychology and the Center for Neuroscience, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Steven F. Maier
Affiliation:
Department of Psychology and the Center for Neuroscience, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Leslie A. Leinwand
Affiliation:
Department of Molecular, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Linda R. Watkins
Affiliation:
Department of Psychology and the Center for Neuroscience, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
Melissa J. Mahoney
Affiliation:
Department of Chemical and Biological Engineering, Cellular and Developmental Biology, University of CO at Boulder, Boulder, CO 80309, USA
*
Correspondence should be addressed to Erin D. Milligan, Department of Psychology, Campus Box 345, University of Colorado at Boulder, Boulder, CO 80309-0345, USA phone: +1 303 735 2295 fax: +1 303 492 2967 email: erin.milligan@colorado.edu
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Abstract

Research on communication between glia and neurons has increased in the past decade. The onset of neuropathic pain, a major clinical problem that is not resolved by available therapeutics, involves activation of spinal cord glia through the release of proinflammatory cytokines in acute animal models of neuropathic pain. Here, we demonstrate for the first time that the spinal action of the proinflammatory cytokine, interleukin 1 (IL-1) is involved in maintaining persistent (2 months) allodynia induced by chronic-constriction injury (CCI). The anti-inflammatory cytokine IL-10 can suppress proinflammatory cytokines and spinal cord glial amplification of pain. Given that IL-1 is a key mediator of neuropathic pain, developing a clinically viable means of long-term delivery of IL-10 to the spinal cord is desirable. High doses of intrathecal IL-10-gene therapy using naked plasmid DNA (free pDNA-IL-10) is effective, but the dose required limits its potential clinical utility. Here we show that intrathecal gene therapy for neuropathic pain is improved sufficiently using two, distinct synthetic polymers, poly(lactic-co-glycolic) and polyethylenimine, that substantially lower doses of pDNA-IL-10 are effective. In conclusion, synthetic polymers used as i.t. gene-delivery systems are well-tolerated and improve the long-duration efficacy of pDNA-IL-10 gene therapy.

Keywords

Gliaratsallodyniachronic constriction injuryneuropathic painpolymer plasmid-DNAgene therapy
Type
Research Article
Information
Neuron Glia Biology , Volume 2 , Issue 4 , November 2006 , pp. 293 - 308
Copyright
Copyright © Cambridge University Press 2007

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Footnotes

*

This gene has a point mutation (F129S) as described in the Methods section.

References

* This gene has a point mutation (F129S) as described in the Methods section.