Clarification of Mechanism of Anti-microRNA-122 Therapy for Hepatitis C Virus Infection

• Project/Area Number: 24790687
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kanazawa University
• Principal Investigator: SHIMAKAMI Tetsuro 金沢大学, 大学病院, 助教 (50436820)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: C型肝炎ウイルス / microRNA-122 / C型慢性肝炎 / 抗ウイルス療法 / マイクロRNA122

Outline of Final Research Achievements

The emergence of Direct-Acting Antiviral Agents (DAA)-resistant virus could be a serious problem for the treatment of chronic hepatitis C patients. We examined the efficiency of the combination therapy with DAA and anti-miR-122 therapy, which is targeting liver-specific miRNA, miR-122. We demonstrated that the combination therapy (1) shows synergistic antiviral effect, (2) alleviates the drug resistance of DAA-resistance viruses, and (3)completely inhibits the emergence of DAA-resistance virus. These results indicate that anti-miR-122 therapy is quite useful in terms of inhibiting the emergence of DAA-resistance virus when it is combined with DAA.

Research Products

• [Journal Article] Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C. (2015)
  • Author(s): Selitsky SR, Baran-Gale J, Honda M, Yamane D, Masaki T, Fannin EE, Guerra B, Shirasaki T, Shimakami T, Kaneko S, Lanford RE, Lemon SM, Sethupathy P.
  • Journal Title: Sci Rep. Volume: 5 Issue: 1 Pages: 7675-7675
  • DOI: 10.1038/srep07675
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of the hepatitis C virus RNA replicase by (2014)
  • Author(s): Yamane D, McGivern DR, Wauthier E, Yi M, Madden VJ, Welsch C, Antes I, Wen Y, Chugh PE, McGee CE, Widman DG, Misumi I, Bandyopadhyay S, Kim S, Shimakami T, Oikawa T, Whitmire JK, Heise MT, Dittmer DP, Kao CC, Pitson SM, Merrill AH Jr, Reid LM, Lemon SM.
  • Journal Title: Nature Medicine Volume: 20 Issue: 8 Pages: 927-35
  • DOI: 10.1038/nm.3610
  • Peer Reviewed
• [Journal Article] Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway. (2014)
  • Author(s): Shirasaki T, Honda M, Shimakami T, Murai K, Shiomoto T, Okada H, Takabatake R, Tokumaru A, Sakai Y, Yamashita T, Lemon SM, Murakami S, Kaneko S.
  • Journal Title: Hepatology. Volume: 60(5) Issue: 5 Pages: 1519-30
  • DOI: 10.1002/hep.27277
  • Peer Reviewed
• [Journal Article] The acyclic retinoid peretinoin inhibits hepatitis C virus replication and infectious virus release in vitro. (2014)
  • Author(s): Shimakami T, Honda M, Shirasaki T, Takabatake R, Liu F, Murai K, Shiomoto T, Funaki M, Yamane D, Murakami S, Lemon SM, Kaneko S.
  • Journal Title: Sci Rep. Volume: 4 Issue: 1 Pages: 4688-4688
  • DOI: 10.1038/srep04688
  • NAID: 120005774911
  • Peer Reviewed / Open Access
• [Journal Article] hnRNP L and NF90 interact with hepatitis C virus 5'-terminal untranslated RNA and promote efficient replication. (2014)
  • Author(s): Li Y, Masaki T, Shimakami T, Lemon SM.
  • Journal Title: Journal of Virology Volume: 88 Issue: 13 Pages: 7199-209
  • DOI: 10.1128/jvi.00225-14
  • Peer Reviewed
• [Journal Article] microRNA-122 Abundance in Hepatocellular Carcinoma and Non-Tumor Liver Tissue from Japanese Patients with Persistent HCV versus HBV Infection. (2013)
  • Author(s): Spaniel C, Honda M, Selitsky SR, Yamane D, Shimakami T, Kaneko S, Lanford RE, Lemon SM.
  • Journal Title: PLoS One Volume: 8(10) Issue: 10 Pages: e76867-e76867
  • DOI: 10.1371/journal.pone.0076867
  • Peer Reviewed
• [Journal Article] Base pairing between hepatitis C virus RNA and microRNA 122 3' of its seed sequence is essential for genome stabilization and production of infectious virus (2012)
  • Author(s): Shimakami T, Yamane D, Welsch C, Hensley L, Jangra RK, Lemon SM
  • Journal Title: Journal of Virology Volume: 86 Pages: 7372-83
  • Peer Reviewed
• [Presentation] Regulation of Hepatitis C Virus Infection by Long Non-Coding RNAs. (2014)
  • Author(s): Shimakami T, Honda M, Shirasaki T, Liu F, Funaki M, Murai K, Shiomoto T, Murakami S, and Kaneko S.
  • Organizer: The Liver Meeting 2014(65th Annual Meeting of the American Association for the Study of Liver Disease)
  • Place of Presentation: ボストン（アメリカ）
  • Year and Date: 2014-11-13 – 2014-11-17
• [Presentation] Regulation of Hepatitis C Virus Infection by Long Non-Coding RNAs. (2014)
  • Author(s): Shimakami T, Honda M, Shirasaki T, Liu F, Funaki M, Murai K, Shiomoto T, Murakami S, and Kaneko S.
  • Organizer: 21st International Symposium on Hepatitis C Viruses
  • Place of Presentation: バンフ（カナダ）
  • Year and Date: 2014-09-07 – 2014-09-11
• [Presentation] IL28B Genotype，ISGs発現量，前治療反応を用いたテラプレビル併用抗HCV 療法における治療効果予測と至適治療期間に関する検討 (2014)
  • Author(s): 島上哲朗、本多政夫、金子周一
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30
• [Presentation] 前治療無効例に対するテラプレビル併用3剤併用療法48週間延長投与に関する検討 (2014)
  • Author(s): 島上哲朗、本多政夫、金子周一
  • Organizer: 第100回日本消化器病学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-23 – 2014-04-26
• [Presentation] ACYCLIC RETINOID, PERETINOIN, INHIBITS HEPATITIS C VIRUS REPLICATION AND INFECTIOUS VIRUS RELEASE IN CELL (2014)
  • Author(s): Shimakami T, Honda M, Shirasaki T, Murakami S, and Kaneko S.
  • Organizer: The 49th Meeting of the European Association for the Study of the Liver
  • Place of Presentation: ロンドン（イギリス）
  • Year and Date: 2014-04-09 – 2014-04-13
• [Presentation] miR-122 stabilizes Hepatitis C Virus RNA by an Ago2-dependent mechanism (2012)
  • Author(s): Tetsuro Shimakami, Daisuke Yamane, Masao Honda, Shuichi Kaneke, and Stanley M Lemon
  • Organizer: The 10th single topic conference (日本肝臓学会）
  • Place of Presentation: 京王プラザホテル（東京都）