• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Therapeutic Application of Genome Editing for Advanced Heart Failure

Research Project

Project/Area Number 16K09500
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular medicine
Research InstitutionOsaka University

Principal Investigator

Shuichiro Higo  大阪大学, 医学系研究科, 寄附講座准教授 (00604034)

Co-Investigator(Kenkyū-buntansha) 彦惣 俊吾  大阪大学, 医学系研究科, 准教授 (30423164)
高島 成二  大阪大学, 生命機能研究科, 教授 (90379272)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords心筋症 / ゲノム編集 / 拡張型心筋症 / 心筋細胞 / 相同組み換え / 循環器 / 心不全
Outline of Final Research Achievements

Although high-throughput sequencing can elucidate the genetic basis of hereditary cardiomyopathy, direct interventions targeting pathological mutations have not been established. Furthermore, it remains uncertain whether homology-directed repair (HDR) is effective in non-dividing cardiomyocytes. Here, we demonstrate that HDR-mediated genome editing using CRISPR/Cas9 is effective in non-dividing cardiomyocytes. Transduction of adeno-associated virus (AAV) containing sgRNA and repair template into cardiomyocytes constitutively expressing Cas9 efficiently introduced a fluorescent protein to the C-terminus of Myl2, independently of DNA synthesis. We sought to repair a pathological mutation in Tnnt2 in cardiomyocytes of cardiomyopathy model mice, and AAV-mediated HDR achieved precise genome correction at a frequency of ~12.5%. Thus, targeted genome replacement via HDR is effective in non-dividing cardiomyocytes, and represents a potential therapeutic tool for targeting cardiomyopathy.

Academic Significance and Societal Importance of the Research Achievements

拡張型心筋症は、心臓が拡大し、収縮する力が徐々に低下して心不全に至る、難治性の疾患である。ゲノム解析技術の進歩により、拡張型心筋症の発症に遺伝子変異が大きく関与することが明らかとなっている。革新的な技術であるCRISPR/Cas9ゲノム編集は、様々な疾患分野への医療応用が期待されている。今回我々は、マウス培養心筋細胞を用いて、心筋細胞においてゲノム編集を用いた正確な遺伝子編集が可能であることを証明した。更に、遺伝子変異をもった心筋症モデルマウスの培養心筋細胞において、約12.5%の効率で遺伝子変異を修復することに成功した。これらの知見は、難治性心筋症に対する治療開発につながることが期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (25 results)

All 2019 2018 2017 2016 Other

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (18 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Book (3 results) Remarks (1 results)

  • [Journal Article] Old-Age Onset Progressive Cardiac Contractile Dysfunction in a Patient with Polycystic Kidney Disease Harboring a <i>PKD1</i> Frameshift Mutation2019

    • Author(s)
      Suwa Yoshinobu、Higo Shuichiro、Nakamoto Kei、Sera Fusako、Kunimatsu Suzuka、Masumura Yuki、Kanzaki Machiko、Mizote Isamu、Mizuno Hiroya、Fujio Yasushi、Hikoso Shungo、Sakata Yasushi
    • Journal Title

      International Heart Journal

      Volume: 60 Issue: 1 Pages: 220-225

    • DOI

      10.1536/ihj.18-184

    • NAID

      130007557187

    • ISSN
      1349-2365, 1349-3299
    • Year and Date
      2019-01-31
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Targeted Genome Replacement via Homology-directed Repair in Non-dividing Cardiomyocytes2017

    • Author(s)
      Ishizu T, Higo S, Masumura Y, Kohama Y, Shiba M, Higo T, Shibamoto M, Nakagawa A, Morimoto S, Takashima S, Hikoso S, Sakata Y.
    • Journal Title

      Sci Rep.

      Volume: 7 Issue: 1 Pages: 9363-9363

    • DOI

      10.1038/s41598-017-09716-x

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Btg2 is a Negative Regulator of Cardiomyocyte Hypertrophy through a Decrease in Cytosolic RNA.2016

    • Author(s)
      Masumura Y, Higo S, Asano Y, Kato H, Yan Y, Ishino S, Tsukamoto O, Kioka H, Hayashi T, Shintani Y, Yamazaki S, Minamino T, Kitakaze M, Komuro I, Takashima S, Sakata Y.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 28592-28592

    • DOI

      10.1038/srep28592

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Medical Application of Genome Editing for Advanced Heart Failure2019

    • Author(s)
      Shuichiro Higo, Yuki Masumura, Shungo Hikoso, Yasushi Sakata
    • Organizer
      第83回日本循環器学会学術集会 プレナリーセッション
    • Related Report
      2018 Annual Research Report
  • [Presentation] Genome Editing Targeting Cardiovascular Disease2019

    • Author(s)
      肥後 修一朗
    • Organizer
      第83回日本循環器学会学術集会 モーニングレクチャー
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Rapid Evaluation of Candidate Causal Gene Mutation using High-content Image Analysis Combined with Targeted Gene Disruption2018

    • Author(s)
      Yuki Masumura, Suzuka Kunimatsu, Shuichiro Higo, Yasuaki Kohama, Mikio Shiba, Takumi Kondo, Masato Shibamoto, Seiji Takashima, Shigeru Miyagawa, Shungo Hikoso, Yasushi Sakata
    • Organizer
      AHA scientific sessions 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome Editing in Cardiomyopathy2018

    • Author(s)
      Shuichiro Higo, Yuki Masumura, Shungo Hikoso, Yasushi Sakata
    • Organizer
      European Society of Cardiology Congress 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Homology-directed Repair-mediated Genome Replacement Targeting Pathological Mutation in Dilated Cardiomyopathy2018

    • Author(s)
      Shuichiro Higo, Takamaru Ishizu, Yuki Masumura, Tomoaki Higo Hikoso Shungo, Sakata Yasushi
    • Organizer
      第9回武田科学振興財団薬科学シンポジウム 医薬応用を目指したゲノム編集
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Presentation] Multiplexed Measurement of Cell-type Specific Calcium Dynamics Using High-content Image Analysis2018

    • Author(s)
      Yuki Masumura, Suzuka Kunimatsu, Shuichiro Higo, Takamaru Ishizu, Yasuaki Kohama, Mikio Shiba, Takumi Kondo, Tomoaki Higo, Masato Shibamoto, Seiji Takashima, Shungo Hikoso, Yasushi Sakata
    • Organizer
      第82回日本循環器学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 高齢期において進行性難治性心不全を呈しPKD1フレームシフト変異が同定された多発性嚢胞腎の1例2018

    • Author(s)
      宮崎友希, 肥後修一朗, 諏訪恵信, 中本敬, 世良英子, 溝手勇, 水野裕八, 藤尾慈, 彦惣俊吾, 坂田泰史
    • Organizer
      医学生研修医の日本内科学会ことはじめ2018京都
    • Related Report
      2018 Annual Research Report
  • [Presentation] ハイコンテントイメージ解析及び ゲノム編集を用いた心筋症遺伝子変異の病原性の迅速な評価系の構築2018

    • Author(s)
      増村雄喜、 國松鈴花、肥後修一朗、小濱康明、志波幹夫、近藤匠巳、肥後友彰、柴本将人、高島成二、宮川繁、彦惣俊吾、坂田泰史
    • Organizer
      第3回心筋症研究会 YIA
    • Related Report
      2018 Annual Research Report
  • [Presentation] Verification of novel molecular mechanism of cardiac hypertrophy via regulation of mRNA degradation2018

    • Author(s)
      Yuki Masumura, Shuichiro Higo, Shungo Hikoso, Seiji Takashima, Yasushi Sakata
    • Organizer
      第2回BCVR
    • Related Report
      2018 Annual Research Report
  • [Presentation] 二度の心停止から蘇生され プラコフィリン2(PKP2)ハプロ不全が同定された 不整脈源性右室心筋症(ARVC)の一例2018

    • Author(s)
      中村聡希, 肥後修一朗, 南口仁, 世良英子, 水野裕八 國松鈴花, 志波幹夫, 高島成二, 彦惣俊吾, 坂田泰史
    • Organizer
      第221回日本内科学会近畿地方会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ゲノム編集の重症心不全医療応用2018

    • Author(s)
      肥後修一朗、増村雄喜、彦惣俊吾、坂田泰史
    • Organizer
      第22回日本心不全学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Development of Homology-directed Repair-mediated Genome Replacement Targeting Pathological Mutation in Cardiomyocytes2018

    • Author(s)
      Takamaru Ishizu, Shuichiro Higo, Shungo Hikoso, Yasushi Sakata
    • Organizer
      第1回日本循環器学会基礎研究フォーラム 基礎研究助成講演
    • Related Report
      2017 Research-status Report
  • [Presentation] Therapeutic Genome Editing Targeting an Upstream Genetic Basis of Advanced Heart Failure2018

    • Author(s)
      Shuichiro Higo, Takamaru Ishizu, Yuki Masumura, Tomoaki Higo, Shungo Hikoso, Yasushi Sakata
    • Organizer
      第82回日本循環器学会学術集会 プレナリーセッション
    • Related Report
      2017 Research-status Report
  • [Presentation] 心筋症遺伝子変異に対する相同組換え修復(HDR)を介したゲノム編集治療の開発2017

    • Author(s)
      石津宜丸 肥後修一朗 志波幹夫 小濱康明 柴本将人 肥後友彰 中川彰人 増村雄喜 森本幸生 彦惣俊吾 坂田泰史
    • Organizer
      第3回心筋症研究会 YIA
    • Related Report
      2017 Research-status Report
  • [Presentation] 拡張型心筋症遺伝子変異に対する相同組換え修復(HDR)を介したゲノム編集治療の開発2017

    • Author(s)
      石津宜丸 肥後修一朗 増村雄喜 小濱康明 志波幹夫 肥後友彰 柴本将人 中川彰人 森本幸生  高島成二 彦惣俊吾 坂田泰史
    • Organizer
      第2回日本ゲノム編集学会
    • Related Report
      2017 Research-status Report
  • [Presentation] Development of Homology-directed Repair-mediated Genome Replacement Targeting Pathological Mutation in Cardiomyocytes2017

    • Author(s)
      Shuichiro Higo, Takamaru Ishizu, Yuki Masumura, Tomoaki Higo,Sachio Morimoto, Seiji Takashima, Shungo Hikoso, Yasushi Sakata
    • Organizer
      AHA scientific sessions 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Clarification of the novel mechanism of cardiomyocyte hypertrophy via regulation of RNA metabolism2016

    • Author(s)
      増村雄喜, 肥後修一朗, 朝野仁裕, 彦惣俊吾, 坂田泰史, 高島成二
    • Organizer
      第33 回ISHR2016
    • Place of Presentation
      東京
    • Year and Date
      2016-12-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Single Cell Imaging Analysis Clarifies Quantitative Kinetics of RNA in Cardiomyocytes2016

    • Author(s)
      増村雄喜, 肥後修一朗, 朝野仁裕, 北風政史, 坂田泰史, 高島成二
    • Organizer
      第89 回日本生化学学会
    • Place of Presentation
      仙台
    • Year and Date
      2016-09-25
    • Related Report
      2016 Research-status Report
  • [Book] 心不全のサイエンス ゲノム編集の難治性心筋症医療応用2019

    • Author(s)
      肥後修一朗
    • Total Pages
      216
    • Publisher
      羊土社
    • ISBN
      9784758103770
    • Related Report
      2018 Annual Research Report
  • [Book] 心不全 ゲノム編集2018

    • Author(s)
      肥後修一朗, 石津宜丸, 坂田泰史
    • Total Pages
      720
    • Publisher
      日本臨牀社
    • Related Report
      2018 Annual Research Report
  • [Book] 医療応用をめざすゲノム編集 拡張型心筋症におけるゲノム編集治療2018

    • Author(s)
      肥後修一朗
    • Total Pages
      274
    • Publisher
      化学同人
    • ISBN
      9784759817294
    • Related Report
      2018 Annual Research Report
  • [Remarks] ゲノム編集技術を用いて拡張型心筋症の遺伝子変異修復に成功

    • URL

      http://www.cardiology.med.osaka-u.ac.jp/?page_id=34515

    • Related Report
      2017 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi