Elucidation of the pathological mechanism of KACh channelopathy and development of novel heart rate modulating drug

• Project/Area Number: 18K19547
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Asano Yoshihiro 大阪大学, 医学系研究科, 講師 (60527670)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 希少難病 / 分子循環器学 / 徐脈性不整脈 / 洞不全症候群 / ゲノム解析 / 創薬開発 / 分子循環器病学 / チャネル遺伝子 / 選択的阻害薬

Outline of Final Research Achievements

We established KACh channelopathy, an inherited bradyarrhythmia consisting of sick sinus syndrome, atrioventricular block, and atrial fibrillation. Whole exome sequencing analysis was performed using a genomic cohort and pathogenic variants were identified among the genes associated with KACh channelopathy. We analysed the molecular mechanism of KACh channel-mediated regulation, assessed its function, and evaluated for drug efficacy by functional analysis and in vivo evaluation.

Academic Significance and Societal Importance of the Research Achievements

遺伝性徐脈性不整脈に対して安全かつ慢性期使用に耐え得る心拍増加薬はなく、侵襲を余儀なくされるペースメーカー等の対症治療に頼らざるを得ない。本研究において徐脈、房室ブロック、心房細動の原因となることを見出し、それらの原因となる遺伝要因を網羅的に探索しそれぞれの機能性変化を明確にすることで、新たな希少難病であるKAChチャネロパチーおよびその関連疾患の疾患概念の確立から臨床診断が可能となる。さらに疾患克服を目指すための治療標的探索を通じて、実臨床に還元できる治療法開発が可能となる。

Research Products

• [Journal Article] In vivo real‐time ATP imaging in zebrafish hearts reveals G0s2 induces ischemic tolerance (2020)
  • Author(s): Kioka Hidetaka、Kato Hisakazu、Fujita Takeshi、Asano Yoshihiro、Shintani Yasunori、Yamazaki Satoru、Tsukamoto Osamu、Imamura Hiromi、Kogo Mikihiko、Kitakaze Masafumi、Sakata Yasushi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 2 Pages: 2041-2054
  • DOI: 10.1096/fj.201901686r
  • Peer Reviewed
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail Volume: 6 Issue: 2 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Journal Article] Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese (2019)
  • Author(s): Ogawa, Kotaro; Okuno, Tatsusada; Hosomichi, Kazuyoshi; Hosokawa, Akiko; Hirata, Jun; Suzuki, Ken; Sakaue, Saori; Kinoshita, Makoto; Asano, Yoshihiro; Miyamoto, Katsuichi
  • Journal Title: Journal of neuroinflammation Volume: 16 Issue: 1 Pages: 162-162
  • DOI: 10.1186/s12974-019-1551-z
  • Peer Reviewed / Open Access
• [Journal Article] A molecular triage process mediated by RING finger protein 126 and BCL2-associated athanogene 6 regulates degradation of G0/G1 switch gene 2 (2019)
  • Author(s): Kamikubo Kenta、Kato Hisakazu、Kioka Hidetaka、Yamazaki Satoru、Tsukamoto Osamu、Nishida Yuya、Asano Yoshihiro、Imamura Hiromi、Kawahara Hiroyuki、Shintani Yasunori、Takashima Seiji
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 40 Pages: 14562-14573
  • DOI: 10.1074/jbc.ra119.008544
  • Peer Reviewed
• [Journal Article] Higd1a improves respiratory function in the models of mitochondrial disorder (2019)
  • Author(s): Nagao Takemasa、Shintani Yasunori、Hayashi Takaharu、Kioka Hidetaka、Kato Hisakazu、Nishida Yuya、Yamazaki Satoru、Tsukamoto Osamu、Yashirogi Shohei、Yazawa Issei、Asano Yoshihiro、Shinzawa‐Itoh Kyoko、Imamura Hiromi、Suzuki Takeo、Suzuki Tsutomu、Goto Yu‐ichi、Takashima Seiji
  • Journal Title: The FASEB Journal Volume: 34 Issue: 1 Pages: 1859-1871
  • DOI: 10.1096/fj.201800389r
  • Peer Reviewed
• [Journal Article] AST-120, an Adsorbent of Uremic Toxins, Improves the Pathophysiology of Heart Failure in Conscious Dogs. (2019)
  • Author(s): Asanuma H, Chung H, Ito S, Min KD, Ihara M, Takahama H, Funayama M, Imazu M, Fukuda H, Ogai A, Asano Y, Minamino T, Takashima S, Morita T, Sugimachi M, Asakura M, Kitakaze M.
  • Journal Title: Cardiovasc Drugs Ther. Volume: 33 Issue: 3 Pages: 277-286
  • DOI: 10.1007/s10557-019-06875-z
  • Peer Reviewed
• [Journal Article] Anti-HB-EGF Antibody-Mediated Delivery of siRNA to Atherosclerotic Lesions in Mice (2018)
  • Author(s): Shota Tsuchida, Takashi Matsuzaki, Masaki Yamato, Keiji Okuda, Hai Ying Fu, Ryo Araki, Shoji Sanada, Hiroshi Asanuma, Yoshihiro Asano, Masanori Asakura, Hiroyuki Hao, Seiji Takashima, Masafumi Kitakaze, Yasushi Sakata, Eisuke Mekada, Tetsuo Minamino
  • Journal Title: International Heart Journal Volume: 59 Issue: 6 Pages: 1425-1431
  • DOI: 10.1536/ihj.17-644
  • NAID: 130007522227
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2018-11-30
  • Peer Reviewed
• [Journal Article] Identification of genetic risk factors of aggressive periodontitis using genomewide association studies in association with those of chronic periodontitis. (2018)
  • Author(s): Masumoto R, Kitagaki J, Fujihara C*, Matsumoto M, Miyauchi S, Asano Y, Imai A, Kobayashi K, Nakaya A, Yamashita M, Yamada S, Kitamura M, Murakami S
  • Journal Title: Journal of Periodontal Research Volume: - Issue: 3 Pages: 12620-12620
  • DOI: 10.1111/jre.12620
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Successful treatment of severe combined post- and pre- capillary pulmonary hypertension in a patient with idiopathic restrictive cardiomyopathy. (2018)
  • Author(s): S. Ishihara, H. Kioka, T. Ohtani, Y. Asano, O. Yamaguchi, S. Hikoso, K. Toda, Y. Saito, Y. Sawa, K. Yamauchi-Takihara, Y. Sakata
  • Journal Title: Pulm Circ Volume: 8 Issue: 3 Pages: 1-5
  • DOI: 10.1177/2045894018770131
  • Peer Reviewed / Open Access
• [Journal Article] How to Eliminate Uncertainty in Clinical Medicine - Clues from Creation of Mathematical Models Followed by Scientific Data Mining. (2018)
  • Author(s): Asano Y.
  • Journal Title: EBioMedicine. Volume: S2352 Pages: 30240-8
  • DOI: 10.1016/j.ebiom.2018.07.001
  • Peer Reviewed / Open Access
• [Presentation] Genome Analysis and Genomic Medicine in Cardiomyopathy (2020)
  • Author(s): Yoshihiro Asano
  • Organizer: 第84回日本循環器学会学術集会（開催延期）
  • Invited
• [Presentation] Genomic medicine in sinus bradycardia and a strategy for development of a novel targeted therapy (2019)
  • Author(s): Yoshihiro Asano
  • Organizer: 2019 XXIII ISHR WORLD CONGRESS（国際心臓研究会世界大会）Symposium
  • Int'l Joint Research / Invited
• [Presentation] Cardiomyopathies: genetic causes and precision medicine (2019)
  • Author(s): Yoshihiro Asano
  • Organizer: ESC CONGRESS 2019（欧州心臓病学会年会）Symposium
  • Int'l Joint Research / Invited
• [Presentation] 心筋症の遺伝子診断における問題点と解決策 (2019)
  • Author(s): 朝野仁裕
  • Organizer: 第23回日本心不全学会学術集会シンポジウム14「心筋症と遺伝子診断」
  • Invited
• [Presentation] Japan Heart Foundation the 44th Sato Memorial Award "Elucidation of the Molecular Mechanism, Establishment of Diagnostic Method, and Drug Development by Omics Analysis of Intractable Cardiovascular Diseases" (2019)
  • Author(s): 朝野仁裕
  • Organizer: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Symposium 17. Precision Medicine in Inherited Arrhythmias "New Insights into the Therapeutic Potential of a KACh Channel in Hereditary Sinus Bradycardia" (2019)
  • Author(s): 朝野仁裕
  • Organizer: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] ミート・ザ・エキスパート 11 心筋症の新しい話題 "Application of Whole Exome Sequencing Data for Detection of Large Genomic Rearrangements in Cardiomyopathy" (2019)
  • Author(s): 朝野仁裕
  • Organizer: The 83rd Annual Scientific Meeting of the Japanese Circulation Society
  • Invited
• [Presentation] 特別企画8「我が国における循環器病研究の現状と将来展望」 (2018)
  • Author(s): 朝野仁裕
  • Organizer: 第22回日本心不全学会
  • Invited
• [Presentation] 第6回日本心不全学会学術賞受賞講演：多層オミックス解析による心不全分子基盤の解明とゲノム医療を目指す診断治療法の開発 (2018)
  • Author(s): 朝野仁裕
  • Organizer: 第22回日本心不全学会
• [Presentation] シンポジウム2「循環器領域における遺伝子診断と遺伝カウンセリング」希少循環器疾患におけるゲノム解析による遺伝子診断 (2018)
  • Author(s): 朝野仁裕
  • Organizer: 第22回日本心不全学会
  • Invited
• [Presentation] シンポジウム5. Practice and Application of Whole Exome Sequencing in Hereditary Heart Disease (2018)
  • Author(s): 朝野仁裕
  • Organizer: The 2nd JCS Council Forum on Basic Cardiovascular Research
  • Invited
• [Presentation] シンポジウム3. ゲノム情報を心筋症診療に生かす「拡張型心筋症における全エクソームシーケンスの応用と展望」 (2018)
  • Author(s): 朝野仁裕
  • Organizer: 第4回心筋症研究会
  • Invited
• [Book] 新心臓病学 第7章心筋疾患・心膜疾患 不整脈原性右室心筋症 (2020)
  • Author(s): 朝野仁裕
  • Publisher: 文光堂
• [Book] CARDIAC PRACTICE 循環器疾患のPrecision Medicine 不整脈Precision Medicineへ向けた試み (2020)
  • Author(s): 朝野仁裕
  • Publisher: メディカルレビュー社
• [Book] 医学のあゆみ 遺伝性心血管疾患のすべて 遺伝性徐脈性不整脈におけるゲノム医療へのアプローチ (2019)
  • Author(s): 朝野仁裕
  • Publisher: 医歯薬出版株式会社
• [Book] 月刊心臓 HEART's Selection 心臓病に挑むゲノム医療 (2019)
  • Author(s): 朝野仁裕
  • Publisher: 日本心臓財団・日本循環器学会（日本医学出版）
• [Book] 月刊心臓 心不全層別化に向けた疾患ゲノム解析 (2019)
  • Author(s): 朝野仁裕
  • Publisher: 日本心臓財団・日本循環器学会（日本医学出版）
• [Patent(Industrial Property Rights)] 遺伝性徐脈性不整脈治療薬 (2019)
  • Inventor(s): 朝野仁裕、髙島成二、山田憲明、山下徹
  • Industrial Property Rights Holder: 朝野仁裕、髙島成二、山田憲明、山下徹
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] 遺伝性徐脈性不整脈治療薬 (2018)
  • Inventor(s): 朝野仁裕、髙島成二、山田憲明、山下徹
  • Industrial Property Rights Holder: 朝野仁裕、髙島成二、山田憲明、山下徹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-247919
  • Filing Date: 2018
  • Overseas