Gene Therapy for Neuropathic Pain by Silencing of TNF-α Expression with Lentiviral Vectors Targeting the Dorsal Root Ganglion in Mice

Nobuhiro Ogawa,Hideto Kojima,Lawrence Chan,Tomoya Terashima,Hiroshi Maegawa,Hiromichi Kawai,Kazuhiro Oka,Simone Di Giovanni

doi:10.1371/journal.pone.0092073

Nobuhiro Ogawa, Hideto Kojima + Show 6 more

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https://doi.org/10.1371/journal.pone.0092073

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Abstract

Neuropathic pain can be a debilitating condition. Many types of drugs that have been used to treat neuropathic pain have only limited efficacy. Recent studies indicate that pro-inflammatory mediators including tumor necrosis factor α (TNF-α) are involved in the pathogenesis of neuropathic pain. In the present study, we engineered a gene therapy strategy to relieve neuropathic pain by silencing TNF-α expression in the dorsal root ganglion (DRG) using lentiviral vectors expressing TNF short hairpin RNA1-4 (LV-TNF-shRNA1-4) in mice. First, based on its efficacy in silencing TNF-α in vitro, we selected shRNA3 to construct LV-TNF-shRNA3 for in vivo study. We used L5 spinal nerve transection (SNT) mice as a neuropathic pain model. These animals were found to display up-regulated mRNA expression of activating transcription factor 3 (ATF3) and neuropeptide Y (NPY), injury markers, and interleukin (IL)-6, an inflammatory cytokine in the ipsilateral L5 DRG. Injection of LV-TNF-shRNA3 onto the proximal transected site suppressed significantly the mRNA levels of ATF3, NPY and IL-6, reduced mechanical allodynia and neuronal cell death of DRG neurons. These results suggest that lentiviral-mediated silencing of TNF-α in DRG relieves neuropathic pain and reduces neuronal cell death, and may constitute a novel therapeutic option for neuropathic pain.

Highlights

Neuropathic pain is defined as pain caused by a lesion or disease in the somatosensory nervous system [1]
tumor necrosis factor a (TNF-a) expression and behavior testing in a spinal nerve transection (SNT) mouse model of neuropathic pain
This study demonstrated that silencing of TNF-a expression with lentiviral vectors suppressed neuropathic pain induced by SNT

Summary

Introduction

Neuropathic pain is defined as pain caused by a lesion or disease in the somatosensory nervous system [1]. Neuropathic pain is characterized by sensory abnormalities that range from unpleasant abnormal sensations (dysesthesia), to an increased response to painful stimuli (hyperalgesia), and to pain in response to a stimulus that does not normally provoke pain (allodynia) [3]. These three kinds of pain are the most difficult types of chronic pain to treat, and are often associated with autoimmune diseases such as rheumatoid arthritis or Sjogren’s syndrome, metabolic diseases such as diabetes mellitus, side effects of drugs for cancer or HIV chemotherapy, toxin exposure, infection and trauma [4,5,6,7]. Available treatments for neuropathic pain include sodium channel blockers, anti-depressants and anti-epileptic drugs, but they are grossly inadequate; novel treatment methods with better efficacy are much needed

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