title: Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice.
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.
authors.affiliation: Department of Medicine, Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: Department of Medicine, Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kawai
authors.affiliation: Department of Medicine, Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
authors.affiliation: Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Department of Medicine, Molecular Genetics in Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maegawa
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000293:injuries / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013119:Spinal Cord Injuries; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D051700:Activating Transcription Factor 3; D015850:Interleukin-6; D009478:Neuropeptide Y; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C103002:Atf3 protein, mouse