Treatment strategy of amyotrophic lateral sclerosis focusing on controlling spinal blood flow and metabolism

• Project/Area Number: 19K07822
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Osaka University
• Principal Investigator: TADA Satoru 大阪大学, 医学系研究科, 招へい教員 (70626530)
• Co-Investigator(Kenkyū-buntansha): 奥野 龍禎 大阪大学, 医学系研究科, 准教授 (00464248) ; 清水 幹人 大阪大学, 医学部附属病院, 医員 (30817507)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); 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: 運動神経変性 / 運動ニューロン疾患 / 低酸素 / 低灌流 / 血管拡張 / 神経変性 / 筋萎縮性側索硬化症 / 低栄養 / 血流改善 / 代謝 / ミトコンドリアDNA / 運動ニューロン病 / 慢性虚血 / 慢性低酸素 / 慢性虚血・低酸素

Outline of Research at the Start

ALSは運動神経が選択的に細胞死を起こす致死的神経変性疾患であり、治療法開発は喫緊の課題である。ALSにおいては低酸素と低栄養が運動ニューロン変性を加速させる可能性が指摘されている。その一方で、運動神経変性に先立って血管変性が生じ、運動神経周囲の血流量が低下することも報告されており、血流低下により運動ニューロンの低酸素、低栄養状態が引き起こされている可能性が示唆される。そのような仮説を元に、我々は本研究において慢性虚血・慢性低酸素改善をターゲットとしたALSの新規治療法開発に臨む。

Outline of Final Research Achievements

To further confirm the mechanism of response to the novel vasodilator (ONO1301) identified in the previous study, HSP70, one of the downstream molecules of HIF1a, a hypoxia-inducing molecule, was confirmed by immunostaining. Specifically, we compared the expression of HSP70 in the spinal cord of ALS model mice treated with ONO1301 and the target treatment group mice, and found that HSP70 signal was reduced in the ONO1301 group, reflecting the improvement in blood flow induced by ONO1301. Based on these findings, the investigators sought to determine whether oral vasodilator X, which is already in clinical use as a vasodilator, could exert a similar neuroprotective effect in ALS model mice.

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症（amyotrophic lateral sclerosis, ALS)は、疾患進行を抑制する根治療法の存在しない神経変性疾患である。人工呼吸器がなければ、患者は発症後３－５年で呼吸不全のため死去するため、その治療法の開発が喫緊の課題である。現在保険適応を受けている治療は２種類存在するが、いずれも患者の生存期間を延長する効果はない。我々の知見により、これらの治療法に加えて血管拡張療法が臨床的に有用である可能性が示唆され、患者寿命を進展できる可能性を見出したことが、本研究の最大の意義である。

Research Products

• [Journal Article] Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder (2022)
  • Author(s): Murata Hisashi、Kinoshita Makoto、Yasumizu Yoshiaki、Motooka Daisuke、Beppu Shohei、Shiraishi Naoyuki、Sugiyama Yasuko、Kihara Keigo、Tada Satoru、Koda Toru、Konaka Hachiro、Takamatsu Hyota、Kumanogoh Atsushi、Okuno Tatsusada、Mochizuki Hideki
  • Journal Title: Neurology - Neuroimmunology Neuroinflammation Volume: 9 Issue: 3
  • DOI: 10.1212/nxi.0000000000001149
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain (2022)
  • Author(s): Sailor Kurt A.、Agoranos George、Lopez-Manzaneda Sergio、Tada Satoru、Gillet-Legrand Beatrix、Guerinot Corentin、Masson Jean-Baptiste、Vestergaard Christian L.、Bonner Melissa、Gagnidze Khatuna、Veres Gabor、Lledo Pierre-Marie、Cartier Nathalie
  • Journal Title: Nature Medicine Volume: 28 Issue: 3 Pages: 517-527
  • DOI: 10.1038/s41591-022-01691-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High cell surface expression and peptide binding affinity of HLA-DQA1*05:03, a susceptible allele of neuromyelitis optica spectrum disorders (NMOSD) (2022)
  • Author(s): Beppu Shohei、Kinoshita Makoto、Wilamowski Jan、Suenaga Tadahiro、Yasumizu Yoshiaki、Ogawa Kotaro、Ishikura Teruyuki、Tada Satoru、Koda Toru、Murata Hisashi、Shiraishi Naoyuki、Sugiyama Yasuko、Kihara Keigo、Sugimoto Tomoyuki、Arase Hisashi、Standley Daron M.、Okuno Tatsusada、Mochizuki Hideki
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-021-04074-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of Memantine in AAV-AD Rat: A Model of Late-Onset Alzheimer’s Disease Predementia (2021)
  • Author(s): Souchet B.、Audrain M.、Alves S.、Fol R.、Tada S.、Orefice N.S、Potier B.、Dutar P.、Billard J.-M.、Cartier N.、Braudeau J.
  • Journal Title: The Journal Of Prevention of Alzheimer's Disease Volume: - Pages: 1-10
  • DOI: 10.14283/jpad.2021.67
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats (2021)
  • Author(s): Ishikura Teruyuki、Kinoshita Makoto、Shimizu Mikito、Murata Hisashi、Beppu Shohei、Koda Toru、Tada Satoru、Miyamoto Katsuichi、Kusunoki Susumu、Sugimoto Tomoyuki、Kumanogoh Atsushi、Okuno Tatsusada、Mochizuki Hideki
  • Journal Title: Journal of Neuroinflammation Volume: 18 Issue: 1 Pages: 1-12
  • DOI: 10.1186/s12974-021-02232-w
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial DNA enhance innate immune responses in neuromyelitis optica by monocyte recruitment and activation (2020)
  • Author(s): Mikito Shimizu, Tatsusada Okuno, Makoto Kinoshita, Hisae Sumi, Harutoshi Fujimura, Kazuya Yamashita, Tomoyuki Sugimoto, Shuhei Sakakibara, Kaori Sakakibara, Toru Koda, Satoru Tada, Teruyuki Ishikura, Hisashi Murata, Shohei Beppu, Naoyuki Shiraishi, Yasuko Sugiyama, Yuji Nakatsuji, Atsushi Kumanogoh & Hideki Mochizuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 13274-13274
  • DOI: 10.1038/s41598-020-70203-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase (2020)
  • Author(s): Koda Toru、Namba Akiko、Kinoshita Makoto、Nakatsuji Yuji、Sugimoto Tomoyuki、Sakakibara Kaori、Tada Satoru、Shimizu Mikito、Yamashita Kazuya、Takata Kazushiro、Ishikura Teruyuki、Murata Syo、Beppu Shohei、Kumanogoh Atsushi、Mochizuki Hideki、Okuno Tatsusada
  • Journal Title: Journal of Neuroinflammation Volume: 17 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s12974-020-01757-w
  • Peer Reviewed / Open Access
• [Presentation] βAPP Processing Drives Gradual Tau Pathology in an Age-Dependent Amyloid Rat Model of Alzheimer's Disease (2019)
  • Author(s): Satoru Tada, Benoit Souchet , Sandro Alves, Romain Fol, Nicola S. Orefice, Nathalie Cartier, Jerome Braudeau, Hideki Mochizuki
  • Organizer: 日本遺伝子治療学会