Therapeutic development based on factors affecting progression and prognosis of amyotrophic lateral sclerosis

• Project/Area Number: 17K09778
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Atsuta Naoki 名古屋大学, 医学部附属病院, 講師 (90547457)
• Co-Investigator(Kenkyū-buntansha): 中村 亮一 名古屋大学, 医学系研究科, 特任助教 (80723030) ; 藤内 玄規 名古屋大学, 医学系研究科, 特任助教 (00748353) ; 勝野 雅央 名古屋大学, 医学系研究科, 教授 (50402566) ; 祖父江 元 名古屋大学, 医学系研究科, 特任教授 (20148315)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 筋萎縮性側索硬化症 / 予後因子 / 予後関連因子 / 治療薬探索

Outline of Final Research Achievements

We identified clinical factors affecting progression and prognosis of ALS patients such as disease type and decline rate of the severity scale (ALSFRS-R). We also identified ADMA/L-arginine ratio in cerebrospinal fluid as a biomarker for predicting prognosis of ALS patients. The gene polymorphisms related to the prognosis of ALS patients were verified, and the novel ALS-related genes were verified in Japanese population. These contribute to therapeutic intervention clues and clinical trial design. In addition, the effects of therapeutic intervention (tracheostomy invasive ventilation therapy), which is difficult to verify in randomized controlled trials, on the prognosis of ALS patients were examined using accumulated longitudinal clinical data.

Academic Significance and Societal Importance of the Research Achievements

神経疾患患者への治療介入は発症からやや時間がたってからの開始となるため、進行、予後に関連する複数の因子への介入が、治療効果を上げるうえで重要である。本研究では、多彩なALS患者の進行予後と関連する因子の解析と同定が行われ、複数のALS関連遺伝子、遺伝子多型の同定、検証が行われた。これらは治療開発の標的としての手がかりや治験を計画する際の登録基準や割付因子として寄与することができる。また、ALS患者に対する治療介入にはランダム化比較試験が難しいものもあるが、その検証に縦断的臨床データを用いた解析が有用であることを示した。

Research Products

• [Journal Article] ALS is a multistep process in South Korean, Japanese, and Australian patients. (2020)
  • Author(s): Vucic S, Higashihara M, Sobue G, Atsuta N, Doi Y, Kuwabara S, Kim SH, Kim I, Oh KW, Park J, Kim EM, Talman P, Menon P, Kiernan MC; PACTALS Consortium.
  • Journal Title: Neurology Volume: 94 Issue: 15
  • DOI: 10.1212/wnl.0000000000009015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cognitive and behavioral status in Japanese ALS patients: a multicenter study. (2020)
  • Author(s): Watanabe Y, Raaphorst J, Izumi Y, Yoshino H, Ito S, Adachi T, Takigawa H, et al.
  • Journal Title: Journal of Neurology Volume: 267 Issue: 5 Pages: 1321-1330
  • DOI: 10.1007/s00415-019-09655-9
  • Peer Reviewed / Open Access
• [Journal Article] Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan (2020)
  • Author(s): Hayashi Naoki、Atsuta Naoki、Yokoi Daichi、Nakamura Ryoichi、Nakatochi Masahiro、Katsuno Masahisa、Izumi Yuishin、Kanai Kazuaki、Hattori Nobutaka、Taniguchi Akira、Morita Mitsuya、Kano Osamu、Shibuya Kazumoto、Kuwabara Satoshi、Suzuki Naoki、Aoki Masashi、Aiba Ikuko、Mizoguchi Kouichi、Oda Masaya、Kaji Ryuji、Sobue Gen
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: 91 Issue: 3 Pages: 285-290
  • DOI: 10.1136/jnnp-2019-322213
  • Peer Reviewed / Open Access
• [Journal Article] 増大特集 ALS2019 ALSにおける患者レジストリの役割-JaCALSなど (2019)
  • Author(s): 熱田 直樹、中村 亮一、林 直毅、藤内 玄規、勝野 雅央、祖父江 元
  • Journal Title: BRAIN and NERVE Volume: 71 Issue: 11 Pages: 1215-1225
  • DOI: 10.11477/mf.1416201431
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2019-11-01
• [Journal Article] Semantic deficits in ALS related to right lingual/fusiform gyrus network involvement (2019)
  • Author(s): Ogura Aya、Watanabe Hirohisa、Kawabata Kazuya、Ohdake Reiko、Tanaka Yasuhiro、Masuda Michihito、Kato Toshiyasu、Imai Kazunori、Yokoi Takamasa、Hara Kazuhiro、Bagarinao Epifanio、Riku Yuichi、Nakamura Ryoichi、Kawai Yoshinari、Nakatochi Masahiro、Atsuta Naoki、Katsuno Masahisa、Sobue Gen
  • Journal Title: EBioMedicine Volume: 47 Pages: 506-517
  • DOI: 10.1016/j.ebiom.2019.08.022
  • Peer Reviewed / Open Access
• [Journal Article] Increase of arginine dimethylation correlates with the progression and prognosis of ALS. (2019)
  • Author(s): Ikenaka K, Atsuta N, Maeda Y, Hotta Y, Nakamura R, Kawai K, Yokoi D, Hirakawa A, Taniguchi A, Morita M, Mizoguchi K, Mochizuki H, Kimura K, Katsuno M, Sobue G.
  • Journal Title: Neurology. Volume: 92 Issue: 16
  • DOI: 10.1212/wnl.0000000000007311
  • Peer Reviewed
• [Journal Article] The Japanese Early-Stage Trial of High-Dose Methylcobalamin for Amyotrophic Lateral Sclerosis (JETALS): Protocol for a Randomized Controlled Trial (2018)
  • Author(s): Oki Ryosuke、Izumi Yuishin、Nodera Hiroyuki、Ishihara Tomohiko，Kaji Ryuji、JETALS et al.
  • Journal Title: JMIR Research Protocols Volume: 7 Issue: 12 Pages: e12046-e12046
  • DOI: 10.2196/12046
  • Peer Reviewed / Open Access
• [Journal Article] Age-related impairment in Addenbrooke's cognitive examination revised scores in patients with amyotrophic lateral sclerosis. (2018)
  • Author(s): Masuda M, Watanabe H, Tanaka Y, Ohdake R, Ogura A, Yokoi T, Imai K, Kawabata K, Riku Y, Hara K, Nakamura R, Atsuta N, Katsuno M, Sobue G.
  • Journal Title: Amyotroph Lateral Scler Frontotemporal Degener. Volume: Epub ahead of print Issue: 7-8 Pages: 1-7
  • DOI: 10.1080/21678421.2018.1510009
  • Peer Reviewed
• [Journal Article] Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. (2018)
  • Author(s): Fujimori K, Ishikawa M, Otomo A, Atsuta N, Nakamura R, Akiyama T, Hadano S, Aoki M, Saya H, Sobue G, Okano H.
  • Journal Title: Nat Med. Volume: 24 Issue: 10 Pages: 1579-1589
  • DOI: 10.1038/s41591-018-0140-5
  • Peer Reviewed
• [Journal Article] Corpus callosal involvement is correlated with cognitive impairment in multiple system atrophy. (2018)
  • Author(s): Hara K, Watanabe H, Bagarinao E, Kawabata K, Yoneyama N, Ohdake R, Imai K, Masuda M, Yokoi T, Ogura A, Tsuboi T, Ito M, Atsuta N, Niwa H, Taoka T, Maesawa S, Naganawa S, Katsuno M, Sobue G.
  • Journal Title: J Neurol. Volume: 265 Issue: 9 Pages: 2079-2087
  • DOI: 10.1007/s00415-018-8923-7
  • Peer Reviewed / Open Access
• [Journal Article] Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis (2018)
  • Author(s): Tohnai Genki、Nakamura Ryoichi、Sone Jun、Nakatochi Masahiro、Yokoi Daichi、Katsuno Masahisa、Watanabe Hazuki、Watanabe Hirohisa、Ito Mizuki、Li Yuanzhe、Izumi Yuishin、et al. Atsuta Naoki、Sobue Gen
  • Journal Title: Neurobiology of Aging Volume: 64 Pages: 158.e15-158.e19
  • DOI: 10.1016/j.neurobiolaging.2017.12.005
  • Peer Reviewed
• [Journal Article] Citrullination of RGG Motifs in FET Proteins by PAD4 Regulates Protein Aggregation and ALS Susceptibility (2018)
  • Author(s): Tanikawa Chizu、Ueda Koji、Suzuki Akari、Iida Aritoshi、Nakamura Ryoichi、Atsuta Naoki、Tohnai Genki、Sobue Gen、Saichi Naomi、Momozawa Yukihide、Kamatani Yoichiro、Kubo Michiaki、Yamamoto Kazuhiko、Nakamura Yusuke、Matsuda Koichi
  • Journal Title: Cell Reports Volume: 22 Issue: 6 Pages: 1473-1483
  • DOI: 10.1016/j.celrep.2018.01.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural MRI correlates of amyotrophic lateral sclerosis progression (2017)
  • Author(s): Senda Joe、Atsuta Naoki、Watanabe Hirohisa、Bagarinao Epifanio、Imai Kazunori、Yokoi Daichi、Riku Yuichi、Masuda Michihito、Nakamura Ryoichi、Watanabe Hazuki、Ito Mizuki、Katsuno Masahisa、Naganawa Shinji、Sobue Gen
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: 88 Issue: 11 Pages: 901-907
  • DOI: 10.1136/jnnp-2016-314337
  • NAID: 120006375888
  • Peer Reviewed
• [Presentation] Prognosis and clinical features of ALS patients in Japan (2019)
  • Author(s): Naoki Atsuta
  • Organizer: 30th International Symposium on ALS/MND
  • Int'l Joint Research
• [Presentation] ALS患者の生存期間に与える非侵襲的換気補助療法の影響―レジストリを用いた解析 (2019)
  • Author(s): 熱田直樹
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] ALSFRS-Rを用いた 筋萎縮性側索硬化症患者の 進行、予後予測と治験デザイン (2018)
  • Author(s): 熱田直樹、中村亮一、林直毅、横井大知、伊藤瑞規、渡辺宏久、勝野雅央、和泉唯信、森田光哉、谷口彰、織田雅也、阿部康二、狩野修、桑原聡、青木正志、金井数明、服部信孝、梶龍兒、祖父江元、JaCALS
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] Prognosis of Japanese patients with amyotrophic lateral sclerosis according to motor phenotype (2018)
  • Author(s): Naoki Atsuta, Daichi Yokoi, Ryoichi Nakamura, Hazuki Watanabe, Naoki Hayashi, Mizuki Ito, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Masaya Oda, Koji Abe, Kouichi Mizoguchi, Osamu Kano, Satoshi Kuwabara, Masashi Aoki, Nobutaka Hattori, Ryuji Kaji, & Gen Sobue, JaCALS
  • Organizer: PACTALS 2018
  • Int'l Joint Research
• [Presentation] Prognosis of Japanese patients with amyotrophic lateral sclerosis according to motor phenotype (2017)
  • Author(s): Naoki Atsuta, Daichi Yokoi, Ryoichi Nakamura, Hazuki Watanabe, Naoki Hayashi, Mizuki Ito, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Mitsuya Morita, Akira Taniguchi, Masaya Oda, Koji Abe, Kouichi Mizoguchi, Osamu Kano, Satoshi Kuwabara, Masashi Aoki, Nobutaka Hattori, Ryuji Kaji, & Gen Sobue, JaCALS
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research