Development of a novel therapeutic drug for the treatment of heart failure by cell protection

• Project/Area Number: 20K21600
• 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: Kyoto University
• Principal Investigator: Ono Koh 京都大学, 医学研究科, 准教授 (00359275)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: ATP / 心不全 / 心筋梗塞 / 心肥大

Outline of Research at the Start

現在の心筋梗塞の治療には、経皮的冠動脈インターベンション(PCI)が行われるが、PCI後の再灌流障害や心筋細胞死を標的とした治療法は皆無である。VCP (valosin-containing protein)は、細胞内の主要なATPaseであり、VCPのATPaseの阻害剤(KUS121)は、細胞内のATP減少と細胞死を抑制する作用がある。KUS薬はブタ心筋梗塞モデルにおいて、梗塞巣を63%低下させた。本研究においては、さらに心不全に対する治療効果およびその作用機序を検討する。また、予備的検討からは心肥大の抑制効果も認めているため、左室駆出率の保たれた心不全の治療にもつながる可能性がある。

Outline of Final Research Achievements

In heart failure, ATP levels in cardiomyocytes decrease. Kyoto University substance 121 (KUS121) increases ATP levels in cells. When KUS121 was administered to a mouse model of heart failure, PCr/ATP ratio and left ventricular ejection fraction were rapidly improved after KUS121 administration. In a canine heart failure model, administration of KUS121 also improved left ventricular contractility and reduced end-diastolic pressure. In cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without altering peak Ca2+ levels or contraction time.
KUS121 improves heart failure through a different mechanism than conventional catecholamines and may be a new option for the treatment of heart failure.

Academic Significance and Societal Importance of the Research Achievements

現在、わが国の疾患別死因の中で、心疾患は15.2%を占め、悪性新生物に続いて第2番目となっている。心不全患者は、急性心不全を繰り返してやがて死に至る。その原因としては、急性心不全治療に用いられる薬剤が十分でないことが理由として挙げられる。具体的には、破綻した血行動態を急激に改善させるために、カテコラミンやPDE阻害薬といった強心薬を用いるために、かえって心臓の線維化や慢性期の心機能を悪化させているのが現状である。これまでの検討より、KUS121が急性心不全治療の治療法を根本的に変え、心不全患者の予後を劇的に改善する理想的な薬剤となる可能性がある。

Research Products

• [Journal Article] Public assistance in patients with acute heart failure: a report from the KCHF registry. (2022)
  • Author(s): Nishimoto Y, Kato T, Morimoto T, Taniguchi R, Yaku H, Kuwahara K, Ozasa N, Sato Y, Kimura T, et al.
  • Journal Title: ESC Heart Fail. Volume: 9 Issue: 3 Pages: 1920-1930
  • DOI: 10.1002/ehf2.13898
  • Peer Reviewed / Open Access
• [Journal Article] Incidence, clinical characteristics, and long-term prognosis of postoperative symptomatic venous thromboembolism: a retrospective cohort study. (2022)
  • Author(s): Takeda C, Yamashita Y, Takeuchi M, Yonekura H, Dong L, Hamada M, Hirotsu A, Ono K, Kawakami K, Fukuda K, Morimoto T, Kimura T, Mizota T.
  • Journal Title: BMJ Open. Volume: 12 Issue: 2 Pages: e055090-e055090
  • DOI: 10.1136/bmjopen-2021-055090
  • Peer Reviewed / Open Access
• [Journal Article] Matched comparison of catheter ablation versus conservative management for atrial fibrillation (2022)
  • Author(s): Kawaji Tetsuma、Shizuta Satoshi、Yamaji Kyohei、Tanaka Munekazu、Kitano Kazuki、Aizawa Takanori、Yamagami Shintaro、Komasa Akihiro、Yoshizawa Takashi、Kato Masashi、Yokomatsu Takafumi、Miki Shinji、Ono Koh、Morimoto Takeshi、Kimura Takeshi
  • Journal Title: Heart and Vessels Volume: - Issue: 7 Pages: 1242-1254
  • DOI: 10.1007/s00380-022-02023-0
  • Peer Reviewed / Open Access
• [Journal Article] Current use of inotropes according to initial blood pressure and peripheral perfusion in the treatment of congestive heart failure: findings from a multicentre observational study (2022)
  • Author(s): Nagao K, Kato T, Yaku H, Morimoto T, Inuzuka Y, Tamaki Y, Kuwahara K, Ozasa N, Kimura T, et al.
  • Journal Title: BMJ Open Volume: 12 Issue: 1 Pages: e053254-e053254
  • DOI: 10.1136/bmjopen-2021-053254
  • Peer Reviewed / Open Access
• [Journal Article] Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism (2021)
  • Author(s): Yamashita Yugo、Amano Hidewo、Ono Koh、Kimura Takeshi、the COMMAND VTE Registry Investigators
  • Journal Title: Journal of Thrombosis and Thrombolysis Volume: 53 Issue: 1 Pages: 182-190
  • DOI: 10.1007/s11239-021-02520-5
  • Peer Reviewed
• [Journal Article] Association between serum inflammatory biomarkers and atrial low voltage in patients with atrial fibrillation: A phase 1 FIB-MARK study (2021)
  • Author(s): Kawaji Tetsuma、Ono Koh、Sowa Naoya、Aizawa Takanori、Hojo Shun、Yaku Hidenori、Nakatsuma Kenji、Kaneda Kazuhisa、Kato Masashi、Yokomatsu Takafumi、Shizuta Satoshi、Miki Shinji、Kimura Takeshi
  • Journal Title: IJC Heart & Vasculature Volume: 37 Pages: 100904-100904
  • DOI: 10.1016/j.ijcha.2021.100904
  • Peer Reviewed / Open Access
• [Journal Article] Severity of pulmonary embolism at initial diagnosis and long-term clinical outcomes: From the COMMAND VTE Registry (2021)
  • Author(s): Yamashita Yugo、Morimoto Takeshi、Ono Koh、Kimura Takeshi
  • Journal Title: International Journal of Cardiology Volume: 343 Pages: 107-113
  • DOI: 10.1016/j.ijcard.2021.08.052
  • Peer Reviewed
• [Journal Article] Periprocedural management and clinical outcomes of invasive procedures after venous thromboembolism: from the COMMAND VTE registry (2021)
  • Author(s): Hata Reo、Yamashita Yugo、Ono Koh、Kimura Takeshi、On behalf of COMMAND VTE Registry Investigators
  • Journal Title: Journal of Thrombosis and Thrombolysis Volume: 53 Issue: 2 Pages: 540-549
  • DOI: 10.1007/s11239-021-02564-7
  • Peer Reviewed
• [Journal Article] Difference between Japanese and White patients with acute pulmonary embolism (2021)
  • Author(s): Yamashita Yugo、Bikdeli Behnood、Monreal Manuel、Morimoto Takeshi、Kato Takao、Ono Koh、de Ancos Cristina、L?pez-N??ez Juan J.、Braester Andrei、Mellado Meritxell、Kimura Takeshi
  • Journal Title: Thrombosis Research Volume: 204 Pages: 52-56
  • DOI: 10.1016/j.thromres.2021.06.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Health improvement framework for actionable treatment planning using a surrogate Bayesian model (2021)
  • Author(s): Nakamura Kazuki、Kojima Ryosuke、Uchino Eiichiro、Ono Koh、Yanagita Motoko、Murashita Koichi、Itoh Ken、Nakaji Shigeyuki、Okuno Yasushi
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3088-3088
  • DOI: 10.1038/s41467-021-23319-1
  • NAID: 120007041705
  • Peer Reviewed / Open Access
• [Journal Article] Impact of no, distal, and proximal deep vein thrombosis on clinical outcomes in patients with acute pulmonary embolism: From the COMMAND VTE registry (2021)
  • Author(s): Nishiwaki Shushi、Morita Yusuke、Ono Koh、Inoko Moriaki、Kimura Takeshi
  • Journal Title: Journal of Cardiology Volume: 77 Issue: 4 Pages: 395-403
  • DOI: 10.1016/j.jjcc.2020.10.019
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity. (2021)
  • Author(s): Horie T, Nakao T, Miyasaka Y, Nishino T, Matsumura S, Nakazeki F, Ide Y, Kimura M, Tsuji S, Ruiz Rodriguez R, WatanabeT, Yamasaki T, Xu S, Otani C, Miyagawa S, Matsushita K, Sowa N, Omori A, Tanaka J, Nishimura C, Picciotto MR, Inoue H, Watanabe D, Nakamura K, Sasaki T, Kimura T, Ono K, et al.
  • Journal Title: Nat Commun. Volume: 12 Issue: 1 Pages: 843-843
  • DOI: 10.1038/s41467-021-21107-5
  • NAID: 120006958077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prediction of Coronary Artery Disease by Measurement of Circulating MicroRNA-423-3p Levels (2020)
  • Author(s): Ono Koh
  • Journal Title: Circulation Journal Volume: 84 Issue: 7 Pages: 1062-1063
  • DOI: 10.1253/circj.CJ-20-0478
  • NAID: 130007864260
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-06-25
  • Open Access
• [Journal Article] Functional Non-coding RNAs in Vascular Diseases. (2020)
  • Author(s): Ono K, Horie T, Baba O, Kimura M, Tsuji S, Ruiz Rodriguez R, Sawa M, Kimura T.
  • Journal Title: FEBS Lett. Volume: in press Issue: 22 Pages: 6315-6330
  • DOI: 10.1111/febs.15678
  • Peer Reviewed / Open Access
• [Journal Article] LincRNA alleviates cardiac systolic dysfunction under pressure overload. (2020)
  • Author(s): Kuwabara Y, Tsuji S, Nishiga M, Izuhara M, Ito S, Nagao K, Horie T, Watanabe S, Koyama S, Kiryu H, Nakashima Y, Baba O, Nakao T, Nishino T, Sowa N, Miyasaka Y, Hatani T, Ide Y, Nakazeki F, Kimura M, Yoshida Y, Inada T, Kimura T, Ono K.
  • Journal Title: Commun Biol. Volume: 3 Issue: 1 Pages: 434-434
  • DOI: 10.1038/s42003-020-01164-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity. (2020)
  • Author(s): Kimura M, Horie T, Baba O, Ide Y, Tsuji S, Ruiz Rodriguez R, Watanabe T, Yamasaki T, Otani C, Xu S, Miyasaka Y, Nakashima Y, Kimura T, Ono K.
  • Journal Title: EMBO Reports Volume: 21 Issue: 4
  • DOI: 10.15252/embr.201948389
  • NAID: 120006936405
  • Peer Reviewed / Open Access
• [Presentation] Inhibition of MicroRNA-33b Ameliorates Abdominal Aortic Aneurysm Formation via Suppression of Inflammatory Pathways (2022)
  • Author(s): 1.Koh Ono
  • Organizer: 日本循環器学会
  • Invited
• [Presentation] 非アルコール性脂肪肝炎（NASH）に対する新規核酸医薬の開発 (2022)
  • Author(s): 尾野 亘
  • Organizer: 日本動脈硬化学会
  • Invited
• [Presentation] Non-coding RNA research, from analysis to therapeutic applications (2021)
  • Author(s): 尾野 亘
  • Organizer: 河口湖カンファレンス
  • Invited
• [Presentation] Function of microRNA-33a/b in atherosclerosis-related diseases and systemic metabolism (2021)
  • Author(s): Koh Ono
  • Organizer: The Great Wall International Congress of Cardiology
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of the role of miR-33a/b in atherosclerosis and obesity. Contrast between central and peripheral roles (2021)
  • Author(s): Koh Ono
  • Organizer: The 19th International Symposium on Atherosclerosis (ISA 2021)
  • Int'l Joint Research / Invited
• [Presentation] Function of miR-33a/b in lipid and systemic metabolism (2021)
  • Author(s): Koh Ono
  • Organizer: The 10th International Congress on Lipid & Atherosclerosis
  • Int'l Joint Research / Invited
• [Presentation] Elucidating the involvement and molecular functions of homeotic genes in the pathogenesis of pulmonary hypertension (2020)
  • Author(s): Masahiro Kimura, Kazuki Matsushita, Takahiro Horie, Takeshi Kimura, Koh Ono
  • Organizer: 第4回日本循環器学会基礎研究フォーラム（BCVR）
• [Presentation] Role of microRNAs in Cardiovascular Disease (2020)
  • Author(s): Koh Ono
  • Organizer: 第84回 日本循環器学会
  • Invited
• [Presentation] Long Intergenic Noncoding RNA, Lionheart, Regulates Heart Size and Contributes to the Protection from Pressure Overload Induced Heart Failure (2020)
  • Author(s): Shuhei Tsuji, Yasuhide Kuwabara, Takahiro Horie, Takeshi Kimura, Koh Ono
  • Organizer: 第84回 日本循環器学会
• [Presentation] miR-33b has more impact on the formation of insulin resistance and atherosclerosis than miR-33a (2020)
  • Author(s): Takahiro Horie, Satoshi Koyama, Takeshi Kimura, Koh Ono
  • Organizer: 第84回 日本循環器学会
• [Presentation] HOX遺伝子を介した、新たな血管リモデリング制御機構の解明 (2020)
  • Author(s): 木村 昌弘、堀江貴裕、尾野亘、木村剛
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Book] 循環器疾患 最新の治療2020-2021 (2020)
  • Author(s): 尾野 亘
  • Total Pages: 500
  • Publisher: 南江堂
• [Remarks] 京都大学循環器内科 分子循環器グループ
  • URL: http://kyoto-u-cardio.jp/kisokenkyu/metabolic/
• [Patent(Industrial Property Rights)] 心機能を改善するための組成物 (2021)
  • Inventor(s): 尾野 亘、堀江貴裕、辻 修平、垣塚彰
  • Industrial Property Rights Holder: 尾野 亘、堀江貴裕、辻 修平、垣塚彰
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-211106
  • Filing Date: 2021