Novel treatment for tracheal stenosis by gene therapy and molecular target therapy

• Project/Area Number: 25462699
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Otorhinolaryngology
• Research Institution: National Defense Medical College
• Principal Investigator: Tomifuji Masayuki 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究, 医学教育部医学科専門課程, 講師 (80327626)
• Co-Investigator(Kenkyū-buntansha): KOJI Araki 防衛医科大学校, その他部局, 准教授 (70317220) ; AKIHIRO Shiotani 防衛医科大学校, その他部局, 教授 (80215946)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: tracheal stenosis / laryngeal stenosis / sendai virus / c-myc / FIR / 気管狭窄 / 喉頭狭窄 / 免疫抑制剤 / 喉頭気管狭窄 / 遺伝子治療 / センダイウイルスベクター

Outline of Final Research Achievements

Animal model of laryngeal and tracheal stenosis was established by brushing from tracheostoma. We chose Sendai virus vector (SeV) as a gene transfer method. Gene transfer to laryngotracheal wound was possible by spraying SeV in 3-4 % of wound area. Administration of FIR gene which is a suppressor of c-myc gene carried by SeV improved tracheal stenosis and survival rate. Immunohistochemical staining of c-Myc also showed low expression level by FIR gene administration in layngotracheal brushing model.
Effect of systemic administration of immunosuppressant tacrolimus for prevention of tracheal stenosis was evaluated. Low dose tacrolimus administration showed preventative effect of tracheal stenosis by suppressing calcineurin/ nuclear factor of activated T cell / interleukin 2 pathway.

Research Products

• [Journal Article] Tacrolimus prevents laryngotracheal stenosis in an acute-injury rat model. (2015)
  • Author(s): Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Matsushita K, Shimada H, Shiotani A.
  • Journal Title: Laryngoscope Volume: Feb Issue: 6 Pages: 1-5
  • DOI: 10.1002/lary.25178
  • Peer Reviewed / Open Access
• [Journal Article] センダイウイルスベクターによる気管狭窄の遺伝子治療 (2015)
  • Author(s): 溝上大輔・荒木幸仁・塩谷彰浩
  • Journal Title: 喉頭 27：51 一一・58，2015． Volume: 27 Pages: 51-58
  • NAID: 130005164818
  • Peer Reviewed / Open Access
• [Journal Article] Gene therapy of c-myc suppressor FUSE-binding protein-interacting repressor by Sendai virus delivery prevents tracheal stenosis (2015)
  • Author(s): Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Ueda Y,
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: 1-12
  • DOI: 10.1371/journal.pone.0116279
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A. Composite hyoid bone graft interposition for the treatment of laryngotracheal stenosis (2014)
  • Author(s): Mizokami D, Araki K, Tomifuji M, Mori Y, Shiotani A.
  • Journal Title: ORL J Otorhinolaryngol Relat Spec Volume: 76 Issue: 3 Pages: 147-152
  • DOI: 10.1159/000363576
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 画像診断パーフェクトガイド 読影のポイントとピットフォール】 部位別診断法 喉頭・気管・食道 喉頭・気管外傷 (2014)
  • Author(s): 溝上大輔、冨藤雅之、塩谷彰浩
  • Journal Title: 耳鼻咽喉科 頭頚部外科 Volume: 86 Pages: 234-240
• [Journal Article] Sendai Virus Transgene in a Novel Gene Therapy for Laryngotracheal Disease. (2013)
  • Author(s): Mizokami D, Araki K, Tanaka N, Suzuki H, Tomifuji M, Yamashita T, Inoue M, Hasegawa M, Shiotani A.
  • Journal Title: Laryngoscope Volume: 29 Issue: 7 Pages: 1717-1724
  • DOI: 10.1002/lary.23917
  • Peer Reviewed
• [Presentation] センダイウイルスベクターを用いた気管狭窄の遺伝子治療 (2015)
  • Author(s): 溝上大輔、荒木幸仁、塩谷彰浩
  • Organizer: 第27回日本喉頭科学会総会・学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-09 – 2015-04-10
• [Presentation] センダイウイルスベクターを用いた気管狭窄の遺伝子治療 (2015)
  • Author(s): 溝上大輔 荒木幸仁 塩谷彰浩
  • Organizer: 日本喉頭科学会総会学術講演会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-09
• [Presentation] 非伝播型c-myc転写抑制因子FIR搭載組換えセンダイウイルスベクターによる気管狭窄の遺伝子治療 (2014)
  • Author(s): 溝上 大輔, 荒木 幸仁, 田中 伸明, 鈴木 洋, 山下 拓, 冨藤 雅之, 上田 泰次, 島田 英昭, 松下 一之
  • Organizer: 日本耳鼻咽喉科学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-14 – 2014-05-17
• [Presentation] 非伝播型c-myc転写抑制因子FIR搭載組換えセンダイウイルスベクターによる気管狭窄の遺伝子治療 (2014)
  • Author(s): 溝上大輔 荒木幸仁 田中伸明 鈴木洋 山下拓 冨藤雅之 上田泰次 島田英昭 松下一之 塩谷彰浩
  • Organizer: 第115回日本耳鼻咽喉科学会総会学術講演会
  • Place of Presentation: 福岡
• [Presentation] Tacrolimus Prevent the Development of Laryngo-tracheal stenosis in the Novel Rat model (2013)
  • Author(s): Araki K, Mizokami D, Yamashita T, Tanaka N, Tomifuji M, Shiotani A
  • Organizer: 117th AAO-HNSF Annual Meeting & OTO EXPO
  • Place of Presentation: Vancouver, Canada