Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice
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 t...
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| Veröffentlicht in: | PloS one 2014-03, Vol.9 (3), p.e92073-e92073 |
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| creator | Ogawa, Nobuhiro Kawai, Hiromichi Terashima, Tomoya Kojima, Hideto Oka, Kazuhiro Chan, Lawrence Maegawa, Hiroshi |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0092073 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0092073</identifier><identifier>PMID: 24642694</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activating transcription factor 3 ; Activating Transcription Factor 3 - genetics ; Activating Transcription Factor 3 - metabolism ; Animals ; Apoptosis ; Biology and Life Sciences ; Cell death ; Cell Death - genetics ; Cellular biology ; Cellulose acetate ; Cytomegalovirus ; Diabetes ; Diabetic neuropathy ; Disease Models, Animal ; Dorsal root ganglia ; Drugs ; Expression vectors ; Ganglia, Spinal - injuries ; Ganglia, Spinal - metabolism ; Gene expression ; Gene Expression Regulation ; Gene Silencing ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors ; In vivo methods and tests ; Inflammation ; Interleukin 6 ; Interleukin-6 - antagonists & inhibitors ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Lentivirus - genetics ; Male ; Medicine ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Nervous system ; Neuralgia ; Neuralgia - genetics ; Neuralgia - metabolism ; Neuralgia - pathology ; Neuralgia - therapy ; Neurons - metabolism ; Neurons - pathology ; Neuropathy ; Neuropeptide Y ; Neuropeptide Y - antagonists & inhibitors ; Neuropeptide Y - genetics ; Neuropeptide Y - metabolism ; Pain ; Pain perception ; Pathogenesis ; Plasmids ; Research and Analysis Methods ; RNA, Messenger - antagonists & inhibitors ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; Rodents ; Science ; Signal Transduction ; Spinal Cord Injuries ; Studies ; Tumor Necrosis Factor-alpha - antagonists & inhibitors ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-TNF ; Tumor necrosis factor-α ; Vectors (Biology)</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e92073-e92073</ispartof><rights>2014 Ogawa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ogawa, Nobuhiro</au><au>Kawai, Hiromichi</au><au>Terashima, Tomoya</au><au>Kojima, Hideto</au><au>Oka, Kazuhiro</au><au>Chan, Lawrence</au><au>Maegawa, Hiroshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-03-18</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e92073</spage><epage>e92073</epage><pages>e92073-e92073</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24642694</pmid><doi>10.1371/journal.pone.0092073</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1508464142 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Activating transcription factor 3 Activating Transcription Factor 3 - genetics Activating Transcription Factor 3 - metabolism Animals Apoptosis Biology and Life Sciences Cell death Cell Death - genetics Cellular biology Cellulose acetate Cytomegalovirus Diabetes Diabetic neuropathy Disease Models, Animal Dorsal root ganglia Drugs Expression vectors Ganglia, Spinal - injuries Ganglia, Spinal - metabolism Gene expression Gene Expression Regulation Gene Silencing Gene therapy Genetic Therapy - methods Genetic Vectors In vivo methods and tests Inflammation Interleukin 6 Interleukin-6 - antagonists & inhibitors Interleukin-6 - genetics Interleukin-6 - metabolism Lentivirus - genetics Male Medicine Medicine and Health Sciences Mice Mice, Inbred C57BL Nervous system Neuralgia Neuralgia - genetics Neuralgia - metabolism Neuralgia - pathology Neuralgia - therapy Neurons - metabolism Neurons - pathology Neuropathy Neuropeptide Y Neuropeptide Y - antagonists & inhibitors Neuropeptide Y - genetics Neuropeptide Y - metabolism Pain Pain perception Pathogenesis Plasmids Research and Analysis Methods RNA, Messenger - antagonists & inhibitors RNA, Messenger - genetics RNA, Messenger - metabolism RNA, Small Interfering - genetics RNA, Small Interfering - metabolism Rodents Science Signal Transduction Spinal Cord Injuries Studies Tumor Necrosis Factor-alpha - antagonists & inhibitors Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Tumor necrosis factor-α Vectors (Biology) |
| title | Gene therapy for neuropathic pain by silencing of TNF-α expression with lentiviral vectors targeting the dorsal root ganglion in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-03T05%3A25%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene%20therapy%20for%20neuropathic%20pain%20by%20silencing%20of%20TNF-%CE%B1%20expression%20with%20lentiviral%20vectors%20targeting%20the%20dorsal%20root%20ganglion%20in%20mice&rft.jtitle=PloS%20one&rft.au=Ogawa,%20Nobuhiro&rft.date=2014-03-18&rft.volume=9&rft.issue=3&rft.spage=e92073&rft.epage=e92073&rft.pages=e92073-e92073&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0092073&rft_dat=%3Cproquest_plos_%3E3249832481%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1508464142&rft_id=info:pmid/24642694&rft_doaj_id=oai_doaj_org_article_3325c598e6a640f992e24aace7e17915&rfr_iscdi=true |