Proof-of-concept of nucleic acid medicine for cardiac channelopahy in an animal model

• Project/Area Number: 15K15049
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Furukawa Tetsushi 東京医科歯科大学, 難治疾患研究所, 教授 (80251552)
• Research Collaborator: IHARA Kensuke ; SASANO Tetsuro
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 不整脈 / イオンチャネル / 突然死 / チャネル病 / 核酸医療

Outline of Final Research Achievements

Cardiac channelopathy is a main cause of familiar sudden death; because of lack of efficient therapy, the establishment of novel therapeutic strategy is warrated. I have established an animal model of cardiac channelophy by introducing gain-of-function mutant, with use of which I tried to establish a novel therapeutic strategy of cardiac channelopathy. Originally, I planned to reduce gain-of-function mutant gene using oligonucleic acid. However, oligonucleic acid was mainly introduced into the liver, causing liver toxicity as a side action. Then, I changed our plan to use Crispr/Cas9 genome editing strategy. I was sucdeeded in introducing Crispr/Cas9 vector into cardiomyocytes, genome editing in cardiac myocytes, and modulating cardiac ion channel function.

Research Products

• [Journal Article] Intravital imaging of Ca(2+) signals in lymphocytes of Ca(2+) biosensor transgenic mice: indication of autoimmune diseases before the pathological onset. (2016)
  • Author(s): Yoshikawa S, Usami T, Kikuta J, Ishii M, Sasano T, Sugiyama K, Furukawa T, Nakasho E, Takayanagi H, Tedder TF, Karasuyama H, Miyawaki A, Adachi T.
  • Journal Title: Sci Rep. 2016 Jan 6;6:18738. Volume: 6 Issue: 1 Pages: 18738-18738
  • DOI: 10.1038/srep18738
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b (2016)
  • Author(s): Takahashi K, Sasano T, Sugiyama K, Kurokawa J, Tamura N, Soejima Y, Sawabe M, Isobe M, Furukawa T.
  • Journal Title: J Mol Cell Cardiol. Volume: 90 Pages: 38-46
  • DOI: 10.1016/j.yjmcc.2015.11.034
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oxidative Stress Induced Ventricular Arrhythmia and Impairment of Cardiac Function in <i>Nos1ap</i> Deleted Mice (2016)
  • Author(s): Sugiyama K, Sasano T, Kurokawa J, Takahashi K, Okamura T, Kato N, Isobe M and Furukawa T
  • Journal Title: International Heart Journal Volume: 57 Issue: 3 Pages: 341-349
  • DOI: 10.1536/ihj.15-471
  • NAID: 130005153706
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A distribution analysis of action potential parameters obtained from patch-clamped human stem cell-derived cardiomyocytes. (2016)
  • Author(s): Lopez-Redondo F, Kurokawa J, Nomura F, Kaneko T, Hamada T, Furukawa T, Yasuda K
  • Journal Title: J Pharmacol Sci Volume: 131 Issue: 2 Pages: 141-145
  • DOI: 10.1016/j.jphs.2016.04.015
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel dielectric coagulation identifies hypercoagulability in patients with a high CHADS2 score without atrial fibrillation (2016)
  • Author(s): 99. Hasegawa Y, Hamada S, Nishimura T, Sasaki T, Ebana Y, Kawabata M, Goya M, Isobe M, Koyama T, Furukawa T, Hirao K, Sasano T
  • Journal Title: PLoS ONE Volume: 11 Issue: 6 Pages: e0156557-e0156557
  • DOI: 10.1371/journal.pone.0156557
  • Peer Reviewed / Open Access
• [Journal Article] Partial IK1 blockade destabilizes spiral wave rotation center without inducing wave breakup and facilitates termination of reentrant arrhythmias in ventricles (2016)
  • Author(s): Kushiyama Y, Honjo H, Niwa R, Takanari H, Yamazaki M, Takemoto Y, Sakuma I, Kodama I, Kamiya K
  • Journal Title: American Journal of Physiology Heart and Circulatory Physiology Volume: 311 Issue: 1 Pages: 750-758
  • DOI: 10.1038/srep34198
  • NAID: 120005946586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic variants associated with susceptibility to atrial fibrillation in Japanese population (2016)
  • Author(s): Liu L, Ebana Y, Nitta JI, Takahashi Y, Miyazaki S, Tanaka T, Komura M, Isobe M, Furukawa T
  • Journal Title: Canadean Journal of Cardiology Volume: 33 Issue: 4 Pages: 443-449
  • DOI: 10.1016/j.cjca.2016.10.029
  • Peer Reviewed / Open Access
• [Journal Article] Screening system for drug-induced arrhythmogenic risk combining patch clamp and a heart simulator. (2015)
  • Author(s): Okada J, Yoshinaga T, Kurokawa J, Washio T, Furukawa T, Sawada K, Sugiura S, Hisada T.
  • Journal Title: Sience Advances Volume: 1 Issue: 4
  • DOI: 10.1126/sciadv.1400142
  • Peer Reviewed / Open Access
• [Journal Article] Aromatase knockout mice reveal an impact of estrogen on drug-induced alternation of murine electrocardiography parameters (2015)
  • Author(s): Kurokawa, J., Sasano, T., Kodama, M., Li, M., Ebana, Y., Harada, N., Honda, S.-I., Nakaya, H., & Furukawa, T.
  • Journal Title: J. Toxicol. Sci. Volume: 40 Issue: 3 Pages: 339-348
  • DOI: 10.2131/jts.40.339
  • NAID: 130005068413
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Strategies for heart regeneration: approaches ranging from induced pluripotent stem cells to direct cardiac reprogramming. (2015)
  • Author(s): Yamakawa H, Ieda M.
  • Journal Title: Int Heart J Volume: 56 Issue: 6 Pages: 1-5
  • DOI: 10.1016/j.stemcr.2015.10.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Enhancement of spontaneous activity by HCN4 overexpression in mouse embryonic stem cell-derived cardiomyocytes:A possible biological pacemaker (2015)
  • Author(s): Saito Y, Nakamura K, Yoshida M, Sugiyama H, Ohe T, Kurokawa J, Furukawa T, Takano M, Nagase S, Morita H,. Kusano KF, Ito H.
  • Journal Title: PLoS ONE Volume: 10
  • Peer Reviewed
• [Presentation] 女性ホルモンが心電図QT間隔に与える影響 (2016)
  • Author(s): 田村文弥、家田真樹、鈴木岳之、福田恵一、中谷晴昭、原田信広、古川哲史、 黒川洵子
  • Organizer: 日本適応医 学会学術集会
  • Place of Presentation: 東京コンベンションセンター
  • Year and Date: 2016-12-16
• [Presentation] ヒト iPS由来心筋細胞の動きベクトル解析による抗がん剤心毒性の評価法 (2016)
  • Author(s): 黒川洵子、児玉昌美、高橋健太郎、諫田泰成、古川哲史
  • Organizer: 第26回日 本循環薬理学会
  • Place of Presentation: 信州大学
  • Year and Date: 2016-12-02
• [Presentation] Individual evaluation of whole blood coagulability and factor Xa activity by novel dielectric blood coagulometry (2016)
  • Author(s): Sasano T, Hamada S, Hasegawa Y, Nishimura T, Yoshitake T, Shiohira S, Sasaki T, Kawabata M, Goya M, Isobe M, Furukawa T, Hirao K
  • Organizer: 第63回日本不整脈心電学会学術大会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-07-17
• [Presentation] Common genetic variants indicate the risk of atrial fibrillation in Japanese population (2016)
  • Author(s): Lian Liu, Yusuke Ebana, Jun-ichi Nitta, Yoshihide Takahashi, Shinsuke Miyazaki, Toshihiro Tanaka, Masatoshi Komura, Mitsuaki Isobe, Tetsushi Furukawa.
  • Organizer: 第63回日本不整脈心電学会学術大会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2016-07-16
• [Presentation] トランスジェニックマウスを利用した心筋遅延整流性カリ ウムチャネル分子複合体の探索と解析 (2016)
  • Author(s): 福田俊、児玉昌美、永森收志，五十棲規嘉、藤塚美紀，金井好克，古川哲史， 黒川洵子
  • Organizer: 第134回日本薬理学会関東部会
  • Place of Presentation: 国際医療福祉大学
  • Year and Date: 2016-07-09
• [Presentation] Oxidative Stress Induced Ventricular Arrhythmia and Impairment of Cardiac Function in Nos1ap Deleted Mice (2016)
  • Author(s): Sasano T, Sugiyama K, Kurokawa J, Takahashi K, Okamura T, Kato N, Isobe M, Furukawa T
  • Organizer: The 9th international conference on the biology, chemistry, and therapeutic approach of Nitric Oxide
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-22
• [Presentation] Regulation of cardiac L-type Ca2+ channel via a progesterone receptor (2016)
  • Author(s): Kurokawa J, Kodama M, Furukawa T
  • Organizer: The 9th international conference on the biology, chemistry, and therapeutic approach of Nitric Oxide
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-22
• [Presentation] Gene-Guided Therapy in AF (2016)
  • Author(s): Furukawa T, Liu L, Ebana Y, Nitta J, Takahashi Y, Miyazaki M, Isobe M, Tanaka T
  • Organizer: Heart Rhythm Society's 37th Annual Scientific Sessions
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2016-05-06
  • Int'l Joint Research / Invited
• [Presentation] Contribution of pannexin-1 to cardioprotection and arrhythmogenicity induced by ischemia/reperfusion injury (2016)
  • Author(s): Takahashi K, Sasano T, Sugiyama K, Isobe M, Furukawa T
  • Organizer: The 80th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 仙台国際センター（宮城県/仙台市）
  • Year and Date: 2016-03-18
• [Presentation] The occurrence of ectopy from pulmonary veins in atrial fibrillation in middle-aged women (2016)
  • Author(s): Hayashi Y, Nitta J, Iwasaki T, Lee K, Watanabe K, Hirao T, Kato N, Inamura Y, Suzuki M, Negi K, Satoh A, Yamato T, Matsumurea Y, Asakawa K, Ebana Y, Furukawa T, Gohya M, Hirao K, Isobe M
  • Organizer: The 80th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 仙台国際センター（宮城県/仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Neurl, ubiquitin E3 ligase, contributes to the maintenance of sarcomere structure and the regulation of autophagy (2016)
  • Author(s): Ito S, Ebana Y, Furukawa T
  • Organizer: The 80th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 仙台国際センター（宮城県/仙台市）
  • Year and Date: 2016-03-18
• [Presentation] The genotype of SNPs related whether ectopy is from pulmonary vein or others in atrial fibrillation (2016)
  • Author(s): Hayashi Y, Nitta J, Iwasaki T, Lee K, Watanabe K, Hirao T, Kato N, Inamura Y, Suzuki M, Negi K, Satoh A, Yamato T, Matsumurea Y, Asakawa K, Ebana Y, Furukawa T, Gohya M, Hirao K, Isobe M
  • Organizer: The 80th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 仙台国際センター（宮城県/仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Novel dielectric blood coagulometry can evaluate factor Xa and thrombin activity individually (2016)
  • Author(s): Hamada S, Hasegawa Y, Nishimura T, Furukawa T, Isobe M, Hirao K, Sasano T
  • Organizer: The 80th Annual Scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 仙台国際センター（宮城県/仙台市）
  • Year and Date: 2016-03-18
• [Presentation] トランスジェニックマウスを利用した心筋IKsチャネル分子複合体の網羅的解析 (2016)
  • Author(s): 福田俊、児玉昌美、永森収志、五十嵐規、藤森美紀、金井好克、古川哲史、黒川洵子
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県/横浜市）
  • Year and Date: 2016-03-09
• [Presentation] 内向き整流カリウムチャネルを過剰発現させたヒトiPS由来心筋細胞を用いた薬理作用解析 (2016)
  • Author(s): 林英里奈、木村麗子、李敏、安東朋子、関野祐子、古川哲史、諫田泰成、黒川洵子
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県/横浜市）
  • Year and Date: 2016-03-09
• [Presentation] 胎生マウスの冠血管形成に見られる性差 (2016)
  • Author(s): 児玉昌美、古川哲史、黒川洵子
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県/横浜市）
  • Year and Date: 2016-03-09
• [Presentation] ヒトiPS細胞由来心筋の活動電位形成に関連する遺伝子の定量的発現解析におけるリファレンス遺伝子の選定 (2016)
  • Author(s): 木村麗子、児玉昌美、古谷和春、諫田泰成、倉智嘉久、関野祐子、古川哲史、黒川洵子
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県/横浜市）
  • Year and Date: 2016-03-09
• [Presentation] Functional evaluation of murine cardiomyocytes using motion imaging technique (2016)
  • Author(s): Kurokawa J, Takahashi K, Furukawa T
  • Organizer: 日本安全性薬理研究会
  • Place of Presentation: 東京大学（東京都/文京区）
  • Year and Date: 2016-02-19
• [Presentation] マウス冠血管形成における性差の起源の探索 (2015)
  • Author(s): 児玉昌美、古川哲史、黒川洵子
  • Organizer: 第38回日本分子生物学会・第88回日本成果学会合同大会
  • Place of Presentation: 神戸ポートアイランド（兵庫県/神戸市）
  • Year and Date: 2015-12-02
• [Presentation] iPS cells and arrhythmia mechanism (2015)
  • Author(s): Tetsushi Furukawa
  • Organizer: 2015 8th APHRS
  • Place of Presentation: メルボルン国際会議場メルボルン市（オーストラリア）
  • Year and Date: 2015-11-18
  • Int'l Joint Research / Invited
• [Presentation] Oxidative stress induced ventricular arrhythmia and impairment cardiac function in Nos1ap deleted mice (2015)
  • Author(s): Koji Sugiyama, Tetsuo Sasano, Tetsushi Furukawa
  • Organizer: 2015 8th APHRS
  • Place of Presentation: メルボルン国際会議場メルボルン市（オーストラリア）
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] Study of long QT syndrome type 3 using human iPS cell-derived cardiomyocytes (2015)
  • Author(s): Tetsushi Furukawa, Shiniachi Okata, Shinsuke Yuasa, 他17名
  • Organizer: 第30回不整脈学会学術集会・第32回日本心電学会学術集会
  • Place of Presentation: 国立京都国際会議場（京都府/京都市）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] 心房細動はなぜ慢性化するのか：そのメカニズムと対策 (2015)
  • Author(s): 古川哲史
  • Organizer: 第30回不整脈学会学術集会・第32回日本心電学会学術集会
  • Place of Presentation: 国立京都国際会議場（京都府/京都市）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] 不整脈医が知っておくべきこと (2015)
  • Author(s): 古川哲史
  • Organizer: 第30回不整脈学会学術集会・第32回日本心電学会学術集会
  • Place of Presentation: 国立京都国際会議場（京都府/京都市）
  • Year and Date: 2015-07-28
  • Invited
• [Presentation] 心房細動とアンチエイジング (2015)
  • Author(s): 古川哲史
  • Organizer: 第15回日本抗加齢医学会総会
  • Place of Presentation: 福岡国際会議場（福岡県/福岡市）
  • Year and Date: 2015-05-30
  • Invited
• [Book] 循環器薬の選び方と使い分け (2017)
  • Author(s): 古川哲史
  • Total Pages: 147
  • Publisher: 総合医学社
• [Book] 循環器治療薬パーフェクトガイド (2016)
  • Author(s): 古川哲史
  • Total Pages: 132
  • Publisher: 総合医学社
• [Book] 心臓イオンチャネルA to Z (2015)
  • Author(s): 古川哲史
  • Total Pages: 168
  • Publisher: ライフメディコム
• [Book] 目からウロコの心電図[改訂版] (2015)
  • Author(s): 古川哲史
  • Total Pages: 145
  • Publisher: ライフメディコム
• [Book] そうだったのか！臨床に役立つ心臓の発生・再生 (2015)
  • Author(s): 古川哲史
  • Total Pages: 178
  • Publisher: メディカル・サイエンス・インターナショナル