Development of gene therapy for liver cirrhosis utilizing MMP13

• Project/Area Number: 16K19333
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Niigata University
• Principal Investigator: Yokoo Takeshi 新潟大学, 医歯学総合研究科, 特任助教 (80750629)
• Research Collaborator: OGAWA kohei ; KOBAYASHI yoko (SHINAGAWA yoko) ; KAMIMURA kenya ; OBA yoshihiko ; YOSHINO hideyoshi ; OTSUKA masato ; ODA masafumi ; Liu Dexi ; TERAI shuji
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: 肝硬変 / MMP13 / ハイドロダイナミック遺伝子導入法 / 肝硬変モデルラット / ハイドロダイナミック遺伝子導入 / 肝線維化率 / 遺伝子治療

Outline of Final Research Achievements

MMP13 is one of enzyme, which has the possibility of ameliorating liver fibrosis. We evaluated whether gene therapy using MMP13 could resolve liver cirrhosis of rat. Hydrodynamic gene delivery of MMP13 to the cirrhotic liver showed to suppress progression of liver fibrosis in the rats with continuous stimulation to cause liver inflammation and fibrosis. In addition, the delivery also demonstrated to decrease fibrotic tissue in the rats without the stimulation.

Academic Significance and Societal Importance of the Research Achievements

肝線維化は高度進行例でなければ、肝内の炎症を鎮めることである程度の改善が期待できる。逆に進行した場合には回復が難しいことが知られており、point of no returnなどと表現される。本研究では、MMP13遺伝子導入の炎症が継続する肝内における線維化抑制効果、また、炎症収束後の肝内における線維化改善効果が示されており、肝硬変診療の新たな治療手段となり得ることを示したものであり、今後の肝硬変診療発展の基盤となり得ると考える。

Research Products

• [Journal Article] Nucleic Acid-Based Therapy: Development of a Nonviral-Based Delivery Approach (2019)
  • Author(s): Yokoo Takeshi、Kamimura Kenya、Kanefuji Tsutomu、Suda Takeshi、Terai Shuji
  • Journal Title: In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders Volume: 1 Pages: 3-20
  • DOI: 10.5772/intechopen.80741
  • ISBN: 9781789857177, 9781789857184
  • Peer Reviewed / Open Access
• [Journal Article] Gene Therapy for Pancreatic Diseases: Current Status (2018)
  • Author(s): Kamimura Kenya、Yokoo Takeshi、Terai Shuji
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 11 Pages: 3415-3415
  • DOI: 10.3390/ijms19113415
  • Peer Reviewed / Open Access
• [Journal Article] 臨床応用可能な肝臓選択的核酸医薬送達法の確立 (2018)
  • Author(s): 上村 顕也、横尾 健、寺井 崇二
  • Journal Title: BIO Clinica Volume: 33 Pages: 34-38
  • NAID: 40021797767
• [Journal Article] Efficacy and safety of pancreas-targeted hydrodynamic gene delivery in rats. (2017)
  • Author(s): Ogawa K, Kamimura K (contributed equally and corresponding), Kobayashi Y, Abe H, Yokoo T, Sakai N, Nagoya T, Sakamaki A, Abe S, Hayashi K, Ikarashi S, Kohisa J, Tsuchida M, Aoyagi Y, Zhang G, Liu D, Terai S.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 9 Pages: 80-88
  • DOI: 10.1016/j.omtn.2017.08.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Liver-targeted Hydrodynamic Gene Therapy: Recent Advances in the Technique. (2016)
  • Author(s): Yokoo T, Kamimura K, Abe H, Kobayashi Y, Kanefuji T, Ogawa K, Goto R, Suda T, Oda M, and Terai S.
  • Journal Title: World J Gastroenterol Volume: 22: Issue: 40 Pages: 8862-8868
  • DOI: 10.3748/wjg.v22.i40.8862
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of fibrotic tissue on liver-targeted hydrodynamic gene delivery. (2016)
  • Author(s): Kobayashi Y, Kamimura K, Abe H, Yokoo T, Ogawa K, Shinagawa Y, Goto R, Inoue R, Ohtsuka M, Miura H, Kanefuji T, Suda T, Tsuchida M, Aoyagi Y, Zhang G, Liu D, Terai S.
  • Journal Title: Mol Ther Nucleic Acids Volume: . 5: e359. Pages: 1-8
  • DOI: 10.1038/mtna.2016.63
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Development of Safe and Effective Hydrodynamic Gene Therapy for Liver Diseases - Effects of Fibrotic Tissue on Gene Delivery Efficiency (2017)
  • Author(s): Kenya Kamimura, Yuji Kobayashi, Hiroyuki Abe, Takeshi Yokoo, Masao Ohtsuka, Hiromi Miura, Guisheng Zhang, Dexi Liu, Shuji Terai
  • Organizer: 第23回 日本遺伝子細胞治療学会学術集会
  • Int'l Joint Research
• [Presentation] 肝硬変合併肝癌への遺伝子治療確立に向けた方法論の検討 (2017)
  • Author(s): 上村 顕也, 横尾 健, 阿部 寛幸, 小林 雄司, 小川 光平, 品川 陽子, 酒井 規裕, 坂牧 僚, 阿部 聡司, 山際 訓, 寺井 崇二
  • Organizer: JDDW 2017
• [Presentation] Development of Image-guided, Liver Lobe-specific Hydrodynamic Gene Delivery Method for Gene Therapy in Liver Diseases (2016)
  • Author(s): Kenya Kamimura, Takeshi Yokoo, Shuji Terai, et al
  • Organizer: AASLD 2016
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Therapeutic Effect of Liver-targeted Hydrodynamic Delivery of MMP13 Gene on Liver Fibrosis (2016)
  • Author(s): Kenya Kamimura, Hiroyuki Abe, Yuji Kobayashi, Takeshi Yokoo, Masato Ohtsuka, Hiromi Miura, Satoshi Yamagiwa, Shuji Terai
  • Organizer: 22nd Annual Meeting of JSGCT 2016（日本遺伝子治療学会）
  • Place of Presentation: 虎ノ門ヒルズ (東京都港区)
  • Year and Date: 2016-07-28
  • Int'l Joint Research
• [Presentation] MMP13遺伝子導入による 肝線維化抑制効果 (2016)
  • Author(s): 横尾 健、上村顕也、寺井崇二
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 東京ベイ幕張ホール (千葉県千葉市)
  • Year and Date: 2016-05-19
• [Presentation] 臓器特異的ハイドロダイナミック遺伝子導入法による肝疾患の遺伝子治療 (2016)
  • Author(s): 上村顕也、横尾健、阿部寛幸、小林雄司、大塚正人、三浦浩美、小川光平、品川陽子、井上良介、山際訓、寺井崇二
  • Organizer: 第102回 日本消化器病学会総会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
  • Year and Date: 2016-04-21