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Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain

Gene Therapy volume 20, pages 742–750 (2013)Cite this article

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Abstract

Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67+endomorphin, GAD67+enkephalin or endomorphin+enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

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Acknowledgements

This work was supported by USAF/AFMC FA 7014-10-2-0002, Clinical Gene Therapy.

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Authors and Affiliations

  1. Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Dardinger Laboratory for Neuro-oncology and Neurosciences, Columbus, OH, USA

    Y Wang, M O Nowicki, S Lawler & E A Chiocca

  2. Department of Neuroscience and Center for Brain and Spinal Cord Repair, Columbus, OH, USA

    X Wang & P G Popovich

  3. Division of Neuromuscular Medicine, Department of Neurology, Columbus, OH, USA

    W D Arnold

  4. Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    S A Fernandez & X Mo

  5. Dyamid, Inc., Pittsburgh, PA, USA

    J Wechuk, D Krisky, J Goss & D Wolfe

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  1. Y Wang
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Correspondence to E A Chiocca.

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Competing interests

JW, DK, JG and DW are employees of Diamyd Inc., where HSV1-based vectors used in this study were manufactured. The remaining authors declare no conflict of interest.

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Wang, Y., Nowicki, M., Wang, X. et al. Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain. Gene Ther 20, 742–750 (2013). https://doi.org/10.1038/gt.2012.90

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