Gene therapy for neuropathic pain using dorsal root ganglion-targeted helper-dependent adenoviral vectors with GAD67 expression.

Abstract

Currently available medications for neuropathic pain are of limited efficacy. Moreover, they are administered systemically and are associated with significant side effects. Ideally, one can circumvent systemic side effects if such treatment can be administered by delivery of the therapeutic agent directly to the diseased neurons. Towards this end, we previously reported the production of a recombinant helper-dependent adenovirus (HDAd) armed with a tissue-specific homing peptide to deliver transgenes targeting sensory neurons with high efficacy. To develop an effective gene therapy for neuropathic pain by producing a dorsal root ganglion (DRG)-targeted HDAd vector that specifically expresses glutamic acid decarboxylase (GAD) 67 (HDAd-DRG-GAD67). We produced spinal nerve transection (SNT) mice as a neuropathic pain model and delivered HDAd-DRG-GAD67 by injection into spinal nerve or intrathecally to these animals. We evaluated the therapeutic efficacy by measuring ion channel gene expression and quantifying mechanical allodynia, a representative symptom of neuropathic pain, in treated animals. Glutamic acid decarboxylase expression by HDAd-DRG-GAD67 reduced allodynia significantly in SNT mice. In addition, HDAd-DRG-GAD67 had a much greater transduction efficacy and expressed the therapeutic gene for a much longer time and at a lower dose of viral particles than wild-type HDAd. We found that SNT induced the upregulation of Cav3.2 mRNA in the DRG and GAD67 overexpression suppressed the elevation. Furthermore, the HDAd-DRG-GAD67-induced allodynia amelioration occurred even when we delayed intrathecal delivery of the therapeutic vector to day 7 after SNT. HDAd-mediated DRG-targeted gene therapy delivering GAD67 is an efficacious treatment for neuropathic pain in SNT mice.