Effectiveness of RyR2 inhibitors as antiarrhytmic drugs

• Project/Area Number: 19K07105
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47040:Pharmacology-related
• Research Institution: Juntendo University
• Principal Investigator: Kurebayashi Nagomi 順天堂大学, 医学部, 客員准教授 (50133335)
• Co-Investigator(Kenkyū-buntansha): 森 修一 東京医科歯科大学, 生体材料工学研究所, 助教 (00467630) ; 村山 尚 順天堂大学, 医学部, 先任准教授 (10230012) ; 村越 伸行 筑波大学, 医学医療系, 准教授 (80447218)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: リアノジン受容体 / 不整脈 / 心臓 / カルシウム / ドラッグスクリーニング / 2型リアノジン受容体 / 抗不整脈薬 / ハイスループットスクリーニング / RyR2阻害薬 / カテコラミン誘発性多型性心室頻拍 / モデルマウス / 細胞内カルシウム動態 / 大規模スクリーニング / 筋小胞体

Outline of Research at the Start

異所性の興奮を起点として発生する心室性不整脈は生命を脅かす重篤な疾患であり、慢性心不全や、心筋に存在する種々のイオンチャネルの遺伝的変異によって起こるが、これらに対し現在使われている抗不整脈薬は効果がない事が多い。本研究計画では、異所性興奮の起点となる筋小胞体Ca2+遊離チャネル/2型リアノジン受容体(RyR2)を抑制する薬が新規抗不整脈薬となると仮定し、大規模スクリーニングとその構造展開によりRyR2特異的な阻害薬を開発し、それらが異所性興奮に起因するとされる様々な不整脈にどこまで効果を持つか検討する。

Outline of Final Research Achievements

Lethal arrhythmias caused by hyperactivation of the type 2 ryanodine receptor (RyR2) are predicted to be suppressed by RyR2 inhibitors. However, such RyR2-specific inhibitors do not yet exist, so this needs to be verified. First, we showed that disease-causing RyR2 mutations increase the cytoplasmic Ca2+ dependent RyR2 channel activity (i.e., CICR), which then determines the arrhythmia severity. We then performed high-throughput screening for RyR2 inhibitors followed by structural optimization, and finally found a RyR2-specific and high-affinity CICR inhibitor. In addition, we established validation procedures for antiarrhythmic effects using arrhythmia model mice harboring RyR2 mutations. Our novel RyR2 inhibitor efficiently suppressed arrhythmias in the model mice.

Academic Significance and Societal Importance of the Research Achievements

我々の結果は、これまで不整脈治療薬として存在しなかったRyR2阻害薬が新たなカテゴリーの抗不整脈薬となる可能性を示す。RyR2阻害薬は遺伝性不整脈疾患の特効薬となる可能性があるため、社会的意義は大きい。また、RyR2は中枢神経系など心臓以外の様々な臓器に発現しており、てんかんやアルツハイマー病への関与が提唱されているが、その詳細を研究する手段が少なかった。特異的RyR2阻害薬を世に出すことは、これらの重要な疾患の機序解明にも貢献するため、学術的な意義も大きい。

Research Products

• [Int'l Joint Research] Virginia Commonwealth University(米国)
• [Int'l Joint Research] Virginia Commonwealth University(米国)
• [Journal Article] A reconstituted depolarization-induced Ca2+ release platform for validation of skeletal muscle disease mutations and drug discovery (2022)
  • Author(s): Murayama Takashi、Kurebayashi Nagomi、Numaga-Tomita Takuro、Kobayashi Takuya、Okazaki Satoru、Yamashiro Kyosuke、Nakada Tsutomu、Mori Shuichi、Ishida Ryosuke、Kagechika Hiroyuki、Yamada Mitsuhiko、Sakurai Takashi
  • Journal Title: Journal of General Physiology Volume: 154 Issue: 12
  • DOI: 10.1085/jgp.202213230
  • Peer Reviewed / Open Access
• [Journal Article] Development of a water-soluble ryanodine receptor 1 inhibitor (2022)
  • Author(s): Ishida Ryosuke、Mori Shuichi、Murayama Takashi、Nakamichi Ayaka、Chai Xikun、Kurebayashi Nagomi、Iinuma Hiroto、Kagechika Hiroyuki
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 74 Pages: 117027-117027
  • DOI: 10.1016/j.bmc.2022.117027
  • Peer Reviewed / Open Access
• [Journal Article] Mice with R2509C-RYR1 mutation exhibit dysfunctional Ca2+ dynamics in primary skeletal myocytes (2022)
  • Author(s): Tsuboi Yoshitaka、Oyama Kotaro、Kobirumaki-Shimozawa Fuyu、Murayama Takashi、Kurebayashi Nagomi、Tachibana Toshiaki、Manome Yoshinobu、Kikuchi Emi、Noguchi Satoru、Inoue Takayoshi、Inoue Yukiko U.、Nishino Ichizo、Mori Shuichi、Ishida Ryosuke、Kagechika Hiroyuki、Suzuki Madoka、Fukuda Norio、Yamazawa Toshiko
  • Journal Title: Journal of General Physiology Volume: 154 Issue: 11
  • DOI: 10.1085/jgp.202213136
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of kallikrein‐PAR2‐proinflammatory pathway in severe trastuzumab‐induced cardiotoxicity (2022)
  • Author(s): Sasaki Ritsuko、Kurebayashi Nagomi、Eguchi Hidetaka、Horimoto Yoshiya、Shiga Takahiro、Miyazaki Sakiko、Kashiyama Taku、Akamatsu Wado、Saito Mitsue
  • Journal Title: Cancer Science Volume: 113 Issue: 10 Pages: 3449-3462
  • DOI: 10.1111/cas.15508
  • Peer Reviewed / Open Access
• [Journal Article] Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating (2022)
  • Author(s): Oyama Kotaro、Zeeb Vadim、Yamazawa Toshiko、Kurebayashi Nagomi、Kobirumaki-Shimozawa Fuyu、Murayama Takashi、Oyamada Hideto、Noguchi Satoru、Inoue Takayoshi、Inoue Yukiko U.、Nishino Ichizo、Harada Yoshie、Fukuda Norio、Ishiwata Shin’ichi、Suzuki Madoka
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 119 Issue: 32
  • DOI: 10.1073/pnas.2201286119
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations (2022)
  • Author(s): Kobayashi Takuya、Tsutsumi Akihisa、Kurebayashi Nagomi、Saito Kei、Kodama Masami、Sakurai Takashi、Kikkawa Masahide、Murayama Takashi、Ogawa Haruo
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 2821-2821
  • DOI: 10.1038/s41467-022-30429-x
  • Peer Reviewed / Open Access
• [Journal Article] Cytosolic Ca2+-dependent Ca2+ release activity primarily determines the ER Ca2+ level in cells expressing the CPVT-linked mutant RYR2 (2022)
  • Author(s): Kurebayashi Nagomi、Murayama Takashi、Ota Ryosaku、Suzuki Junji、Kanemaru Kazunori、Kobayashi Takuya、Ohno Seiko、Horie Minoru、Iino Masamitsu、Yamashita Fumiyoshi、Sakurai Takashi
  • Journal Title: Journal of General Physiology Volume: 154 Issue: 9
  • DOI: 10.1085/jgp.202112869
  • Peer Reviewed / Open Access
• [Journal Article] NRSF- GNAO1 Pathway Contributes to the Regulation of Cardiac Ca 2+ Homeostasis (2022)
  • Author(s): Inazumi Hideaki、Kuwahara Koichiro、Nakagawa Yasuaki、et al.
  • Journal Title: Circulation Research Volume: 130 Issue: 2 Pages: 234-248
  • DOI: 10.1161/circresaha.121.318898
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome (2021)
  • Author(s): Hirose Sayako、Murayama Takashi、Tetsuo Naoyuki、Hoshiai Minako、Kise Hiroaki、Yoshinaga Masao、Aoki Hisaaki、Fukuyama Megumi、Wuriyanghai Yimin、Wada Yuko、Kato Koichi、Makiyama Takeru、Kimura Takeshi、Sakurai Takashi、Horie Minoru、Kurebayashi Nagomi、Ohno Seiko
  • Journal Title: EP Europace Volume: 24 Issue: 3 Pages: 497-510
  • DOI: 10.1093/europace/euab250
  • Peer Reviewed / Open Access
• [Journal Article] A novel RyR1-selective inhibitor prevents and rescues sudden death in mouse models of malignant hyperthermia and heat stroke (2021)
  • Author(s): Yamazawa Toshiko、Kobayashi Takuya、Kurebayashi Nagomi、Konishi Masato、Noguchi Satoru、Inoue Takayoshi、Inoue Yukiko U.、et al.
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 4293-4293
  • DOI: 10.1038/s41467-021-24644-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differential effects of the formin inhibitor SMIFH2 on contractility and Ca 2+ handling in frog and mouse cardiomyocytes (2021)
  • Author(s): Sakata Koji、Matsuyama Sho、Kurebayashi Nagomi、Hayamizu Kengo、Murayama Takashi、Nakamura Kunihide、Kitamura Kazuo、Morimoto Sachio、Takeya Ryu
  • Journal Title: Genes to Cells Volume: 26 Issue: 8 Pages: 583-595
  • DOI: 10.1111/gtc.12873
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of endothelin A receptor by a novel, selective receptor antagonist enhances morphine-induced analgesia: Possible functional interaction of dimerized endothelin A and μ-opioid receptors. Biomed Pharmacother. (2021)
  • Author(s): Kuroda Y, Nonaka M, Kamikubo Y, Ogawa H, Murayama T, Kurebayashi N, Sakairi H, Miyano K, Komatsu A, Dodo T, Nakano-Ito K, Yamaguchi K, Sakurai T, Iseki M, Hayashida M, Uezono Y
  • Journal Title: Biomed Pharmacother. Volume: 141 Pages: 111800-111800
  • DOI: 10.1016/j.biopha.2021.111800
  • Peer Reviewed / Open Access
• [Journal Article] Sudden death after inappropriate shocks of implantable cardioverter defibrillator in a catecholaminergic polymorphic ventricular tachycardia case with a novel RyR2 mutation (2021)
  • Author(s): Itoh Hideki、Murayama Takashi、Kurebayashi Nagomi、Ohno Seiko、Kobayashi Takuya、Fujii Yusuke、Watanabe Masaya、Ogawa Haruo、Anzai Toshihisa、Horie Minoru
  • Journal Title: Journal of Electrocardiology Volume: 69 Pages: 111-118
  • DOI: 10.1016/j.jelectrocard.2021.09.015
  • Peer Reviewed / Open Access
• [Journal Article] Purification of Recombinant Wild Type and Mutant Ryanodine Receptors Expressed in HEK293 Cells (2021)
  • Author(s): Hu Yifan、Iyer Kavita、Nayak Ashok、Kurebayashi Nagomi、Murayama Takashi、Samso Montserrat
  • Journal Title: BIO-PROTOCOL Volume: 11 Issue: 15
  • DOI: 10.21769/bioprotoc.4112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced CICR activity reduces ER Ca2+ level in cells expressing CPVT-linked mutant RyR2 (2021)
  • Author(s): Kurebayashi Nagomi、Murayama Takashi、Ohta Ryosaku、Suzuki Junji、Kanemaru Kazunori、Ohno Seiko、Horie Minoru、Iino Masamitsu、Yamashita Fumiyoshi、Sakurai Takashi
  • Journal Title: Biorxiv Volume: -
  • DOI: 10.1101/2021.01.16.426980
  • Open Access
• [Journal Article] Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation (2020)
  • Author(s): Nozaki Y, Kato Y, Uike K, Yamamura K, Kikuchi M, Yasuda M, Ohno S, Horie M, Murayama T, Kurebayashi N, Horigome H
  • Journal Title: Circulation Journal Volume: 84 Issue: 2 Pages: 226-234
  • DOI: 10.1253/circj.CJ-19-0720
  • NAID: 130007789920
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-01-24
  • Peer Reviewed / Open Access
• [Journal Article] Structural mechanism of two gain-of-function cardiac and skeletal RyR mutations at an equivalent site by cryo-EM (2020)
  • Author(s): Iyer Kavita A.、Hu Yifan、Nayak Ashok R.、Kurebayashi Nagomi、Murayama Takashi、Sams? Montserrat
  • Journal Title: Science Advances Volume: 6 Issue: 31 Pages: 0-0
  • DOI: 10.1126/sciadv.abb2964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular basis for gating and regulation of cardiac ryanodine receptor: underlying mechanisms for gain- and loss-of function mutations (2020)
  • Author(s): Kobayashi Takuya、Tsutsumi Akihisa、Kurebayashi Nagomi、Saito Kei、Kodama Masami、Sakurai Takashi、Kikkawa Masahide、Murayama Takashi、Ogawa Haruo
  • Journal Title: Biorxiv Volume: -
  • DOI: 10.1101/2020.11.30.401026
  • Open Access
• [Journal Article] A novel RyR1 inhibitor prevents and rescues sudden death in a mouse model of malignant hyperthermia and heat stroke (2020)
  • Author(s): Yamazawa Toshiko、Kobayashi Takuya、Kurebayashi Nagomi、19人省略、Murayama Takashi
  • Journal Title: Biorxiv Volume: -
  • DOI: 10.1101/2020.07.02.185520
  • Open Access / Int'l Joint Research
• [Journal Article] RyR2 mutation-linked arrhythmogenic diseases and its therapeutic strategies (2020)
  • Author(s): Kurebayashi Nagomi、Murayama Takashi
  • Journal Title: Folia Pharmacologica Japonica Volume: 155 Issue: 4 Pages: 225-229
  • DOI: 10.1254/fpj.20017
  • NAID: 130007867553
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory mechanisms of ryanodine receptor/Ca2+ release channel revealed by recent advancements in structural studies (2020)
  • Author(s): Ogawa Haruo、Kurebayashi Nagomi、Yamazawa Toshiko、Murayama Takashi
  • Journal Title: Journal of Muscle Research and Cell Motility Volume: in press Issue: 2 Pages: 0-0
  • DOI: 10.1007/s10974-020-09575-6
  • Peer Reviewed / Open Access
• [Journal Article] Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics (2020)
  • Author(s): Yamazawa Toshiko、Ogawa Haruo、Murayama Takashi、Yamaguchi Maki、Oyamada Hideto、Suzuki Junji、Kurebayashi Nagomi、Kanemaru Kazunori、Oguchi Katsuji、Sakurai Takashi、Iino Masamitsu
  • Journal Title: The Journal of General Physiology Volume: 152 Issue: 1 Pages: 0-0
  • DOI: 10.1085/jgp.201812235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay (2019)
  • Author(s): Mori Shuichi、Iinuma Hiroto、Manaka Noriaki、Ishigami-Yuasa Mari、Murayama Takashi、Nishijima Yoshiaki、Sakurai Akiko、Arai Ryota、Kurebayashi Nagomi、Sakurai Takashi、Kagechika Hiroyuki
  • Journal Title: European Journal of Medicinal Chemistry Volume: 179 Pages: 837-848
  • DOI: 10.1016/j.ejmech.2019.06.076
  • Peer Reviewed
• [Journal Article] Assays for Modulators of Ryanodine Receptor (RyR)/Ca 2+ Release Channel Activity for Drug Discovery for Skeletal Muscle and Heart Diseases (2019)
  • Author(s): Murayama Takashi、Kurebayashi Nagomi
  • Journal Title: Current Protocols in Pharmacology Volume: 87 Issue: 1 Pages: 0-0
  • DOI: 10.1002/cpph.71
  • Peer Reviewed / Open Access
• [Journal Article] A novel strategy for treatment of cancer cachexia targeting xanthine oxidase in the brain (2019)
  • Author(s): Uzu Miaki、Nonaka Miki、Miyano Kanako、Sato Hiromi、Kurebayashi Nagomi、Yanagihara Kazuyoshi、Sakurai Takashi、Hisaka Akihiro、Uezono Yasuhito
  • Journal Title: Journal of Pharmacological Sciences Volume: 140 Issue: 1 Pages: 109-112
  • DOI: 10.1016/j.jphs.2019.04.005
  • Peer Reviewed / Open Access
• [Presentation] Arrhythmia severity in mouse models harboring RyR2 mutations with varied extent of channel activity (2023)
  • Author(s): Kurebayashi N, Kodama M, Murayama T, Sugihara M, Konishi M, Miura A, Nishio H, Inoue YU, Inoue T, Noguchi S and Sakurai T
  • Organizer: 67th Biophysical Society Annual meeting
  • Int'l Joint Research
• [Presentation] Relationship between disease phenotype and mutant RyR2 channel activity in CPVT mouse models, (2023)
  • Author(s): Kurebayashi N, Kodama M, Murayama T, Sugihara M, Konishi M, Miura A, Nishio H, U-Inoue Y, Inoue T, Satoru N and Sakurai T
  • Organizer: 第100回 日本生理学会大会
• [Presentation] 複数のRyR2変異マウスモデル系統を用いたカテコラミン誘発性多型性心室頻拍（CPVT）に対する抗不整脈薬の評価 (2022)
  • Author(s): 呉林なごみ, 児玉昌美, 村山尚, 杉原匡美, 石井光一郎, 岡部雄太, 村越伸行, 三浦綾, 西尾元, 井上-上野由紀子, 井上高良, 野口悟, 中村衣里, 金井富三夫, 多田昇弘, 櫻井隆
  • Organizer: 第96回 日本薬理学会年会
• [Presentation] DIFFERENTIAL IMPACTS OF ARRHYTHMIA-LINKED LOSS-OF-FUNCTION RYR2 MUTATIONS ON CA2+ SIGNALING IN CARDIAC CELLS. (2022)
  • Author(s): Nagomi Kurebayashi, Takashi Murayama, Naoyuki Tetsuo, Sayako Hirose, Minoru Horie, Seiko Ohno, Takashi Sakurai
  • Organizer: 66th Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] 機能喪失型催不整脈性RyR2変異が引き起こす様々なCa2+動態異常 (2022)
  • Author(s): 呉林 なごみ，村山 尚，哲翁 直之，廣瀬 紗也子，堀江 稔，大野 聖子，櫻井 隆
  • Organizer: 第95回 日本薬理学会年会
• [Presentation] RyR2発現細胞におけるCa2+オシレーションと小胞体Ca2+レベルの調節メカニズム (2022)
  • Author(s): 呉林 なごみ, 村山 尚, 太田亮 作, 山下 富義, 鈴木 純二, 金丸 和典, 飯野 正光, 櫻井 隆
  • Organizer: 第99回 日本生理学会大会
• [Presentation] CPVTモデルマウスに対するRyR2特異的阻害薬の効果 (2021)
  • Author(s): 呉林なごみ, 村山尚, 石井光一郎, 小西真人, 杉原匡美, 森修一, 飯沼大翔, 湯浅磨里, 村越伸行, 影近弘之, 櫻井隆
  • Organizer: 第94回 日本薬理学会年会
• [Presentation] Search for RyR2 inhibitors and verification of their effects on arrhythmogenic myocardium (2021)
  • Author(s): 呉林なごみ
  • Organizer: 第126回日本解剖学会・第98回日本生理学会合同大会
  • Invited
• [Presentation] 不整脈疾患におけるRyR2の異常とCICR. (2020)
  • Author(s): 呉林なごみ
  • Organizer: 第93回 日本薬理学会年会
  • Invited
• [Presentation] Effects of novel RyR2 inhibitors on cardiac myocytes from diseased hearts (2020)
  • Author(s): Nagomi Kurebayashi, Takashi Murayama, Masato Konishi, Shuichi Mori, Mari Ishigami-Yuasa, Hiroyuki Kagechika, Haruo Ogawa, Sachio Morimoto, Takashi Sakurai
  • Organizer: 63th Annual Meeting of the Biophysical Society
  • Int'l Joint Research
• [Presentation] 不整脈疾患におけるRyR2の異常とCICR (2020)
  • Author(s): 呉林なごみ
  • Organizer: 第93回 日本薬理学会年会
  • Invited
• [Presentation] Mechanism and therapeutic strategies for arrhythmogenic diseases caused by RyR2 mutations (2019)
  • Author(s): Nagomi Kurebayashi
  • Organizer: 9th FAOPS Congress, Symposium25 Calcium signaling in heart disease
  • Int'l Joint Research / Invited
• [Presentation] Ryanodine receptor type 2 as a potential target for novel anti-arrhythmic drugs (2019)
  • Author(s): Kurebayashi, N
  • Organizer: The 71th Annual Meeting of the Korean Physiological Society
  • Int'l Joint Research / Invited
• [Remarks] 順天堂大学大学院 細胞・分子薬理学
  • URL: http://pharmacology.sakura.ne.jp/
• [Remarks] 順天堂大学大学院 細胞・分子薬理学 業績
  • URL: http://pharmacology.sakura.ne.jp/jp/publication.html
• [Remarks] リサーチマップ
  • URL: https://researchmap.jp/read0025294
• [Remarks] リサーチマップ 呉林なごみ
  • URL: https://researchmap.jp/read0025294
• [Remarks] ResearchMap 呉林なごみ
  • URL: https://researchmap.jp/read0025294/
• [Remarks] 順天堂大学大学院 細胞・分子薬理学 ホームページ
  • URL: http://pharmacology.sakura.ne.jp/
• [Patent(Industrial Property Rights)] ２型リアノジン受容体活性抑制剤 (2022)
  • Inventor(s): 國廣なごみ、村山尚、影近 弘之、森 修一、湯浅 磨里、飯沼 大翔
  • Industrial Property Rights Holder: 順天堂大学、東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2022
  • Overseas
• [Patent(Industrial Property Rights)] ２型リアノジン受容体活性抑制剤 (2021)
  • Inventor(s): 国広なごみ、村山 尚、影近弘之、森修 一、湯浅磨里、飯沼大翔
  • Industrial Property Rights Holder: 国広なごみ、村山 尚、影近弘之、森修 一、湯浅磨里、飯沼大翔
  • Industrial Property Rights Type: 特許
  • Filing Date: 2021
  • Overseas
• [Patent(Industrial Property Rights)] ２型リアノジン受容体活性抑制剤 (2020)
  • Inventor(s): 国広なごみ、村山尚、影近弘之、森修一、湯浅磨里、飯沼大翔
  • Industrial Property Rights Holder: 順天堂大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-020656
  • Filing Date: 2020