Development of a novel treatment for SMA using SMA-iPSCs disease models with different genetic background

• Project/Area Number: 16K10008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: 独立行政法人国立病院機構長良医療センター(臨床研究部)
• Principal Investigator: FUNATO Michinori 独立行政法人国立病院機構長良医療センター(臨床研究部), 長良医療センター臨床研究部, 第二小児科医長 (30420350)
• Research Collaborator: OHUCHI Kazuki ; ANDO Shiori ; SATO Arisu
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 疾患モデル / iPS細胞 / 薬剤応答性 / 治療薬開発 / 創薬 / 薬剤反応性 / 神経科学 / 再生医学

Outline of Final Research Achievements

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons. This disease is caused by the deletion of the survival motor neuron protein. Currently, there are no curative agents for SMA, although some research groups have developed treatments based on the molecular pathophysiology of this disease. Our purpose in this study is to establish a number of human SMA with different genetic background-derived induced pluripotent stem cells (SMA-iPSCs) disease model and develop a standard treatment for SMA.
Before now, we established SMA-iPSCs disease models derived from 19 SMA patients with different genetic background. In addition, we assayed a therapeutic drug of thyrotropin-releasing hormone (TRH) analog, a free radical scavenger (edaravone), a docosahexaenoic acid, γ-secretase inhibitor, and rufinamide.

Academic Significance and Societal Importance of the Research Achievements

SMAは難治性の希少疾患ではあるが、背景にひそむ病態は多種多様である。本研究によって、薬剤の応答性の個人差が解明されれば、希少疾患におけるテーラーメイド医療へのさらなる道筋を提示することになる。

Research Products

• [Journal Article] Impairment of oligodendrocyte lineages in Spinal Muscular Atrophy Model Systems (2019)
  • Author(s): Ohuchi K, Funato M, Ando S, Inagaki S, Sato A, Kawase C, Seki J, Nakamura S, Shimazawa M, Kaneko H and Hara H
  • Journal Title: NeuroReport Volume: 30(5) Issue: 5 Pages: 350-357
  • DOI: 10.1097/wnr.0000000000001206
  • Peer Reviewed / Open Access
• [Journal Article] Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems (2019)
  • Author(s): Ohuchi Kazuki、Funato Michinori、Yoshino Yuta、Ando Shiori、Inagaki Satoshi、Sato Arisu、Kawase Chizuru、Seki Junko、Saito Toshio、Nishio Hisahide、Nakamura Shinsuke、Shimazawa Masamitsu、Kaneko Hideo、Hara Hideaki
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 3710-3710
  • DOI: 10.1038/s41598-019-39788-w
  • Peer Reviewed / Open Access
• [Journal Article] The Protective Effects of Levetiracetam on a Human iPSCs-Derived Spinal Muscular Atrophy Model. (2019)
  • Author(s): Ando S, Funato M, Ohuchi K, Inagaki S, Sato A, Seki J, Kawase C, Saito T, Nishio H, Nakamura S, Shimazawa M, Kaneko H, Hara H.
  • Journal Title: Neurochem Res. Volume: in press Issue: 7 Pages: 1773-1779
  • DOI: 10.1007/s11064-019-02814-4
  • Peer Reviewed / Open Access
• [Journal Article] A docosahexaenoic acid-derived pro-resolving agent, maresin 1, protects motor neuron cells death (2018)
  • Author(s): Ohuchi K., Ono Y., Joho M., Tsuruma K., Ogami S., Yamane S., Funato M., Kaneko H., Nakamura S., Hara H. and Shimazawa M
  • Journal Title: Neurochemical Research Volume: 43(7) Issue: 7 Pages: 1413-1423
  • DOI: 10.1007/s11064-018-2556-1
  • Peer Reviewed / Open Access
• [Journal Article] Edaravone is a candidate agent for spinal muscular atrophy: In vitro analysis using a human induced pluripotent stem cells-derived disease model. (2017)
  • Author(s): Ando S, Funato M, Ohuchi K, Kameyama T, Inagaki S, Seki J, Kawase C, Tsuruma K, Shimazawa M, Kaneko H, Hara H.
  • Journal Title: Eur J Pharmacol. Volume: 814 Pages: 161-168
  • DOI: 10.1016/j.ejphar.2017.08.005
  • Peer Reviewed / Open Access
• [Presentation] The protective effects of levetiracetam on spinal muscular atrophy models. (2018)
  • Author(s): Ando S., Ohuchi K., Funato M., Nakamura S., Shimazawa M., Kaneko H. and Hara H.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Skeletal muscle atrophy and impaired myogenesis in spinal muscular atrophy. (2018)
  • Author(s): Ando S., Ohuchi K., Funato M., Nakamura S., Shimazawa M., Kaneko H. and Hara H.
  • Organizer: 1st Global Congress of Pharmacy Faculties
  • Int'l Joint Research
• [Presentation] The neuroprotective effects of edaravone in generated spinal motor neuron using iPSCs derived from a spinal muscular atrophy patient (2017)
  • Author(s): Shiori Ando, Michinori Funato, Kazuki Ohuchi, , Kazuhiro Tsuruma, Masamitsu Shimazawa, Hideo Kaneko, and Hideaki Hara
  • Organizer: the 14th Asian and Oceanian Congress of Child Neurology (AOCCN2017)
  • Place of Presentation: Fukuoka
  • Year and Date: 2017-05-11
  • Int'l Joint Research
• [Presentation] The Protective Effects of Edaravone in Generated Spinal Motor Neuron Using iPSCs Derived from a Spinal Muscular Atrophy Patient (2017)
  • Author(s): Ando S., Funato M., Ohuchi K., Tsuruma K., Shimazawa M., Kaneko H. and Hara H.
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] 脊髄性筋萎縮症病態におけるグリア系譜細胞の分化異常の関与 (2016)
  • Author(s): 大内一輝、舩戸道徳、川瀬千鶴、関順子、安藤栞、稲垣賢、鶴間一寛、嶋澤雅光、金子英雄、原英彰
  • Organizer: 第130回日本薬理学会近畿部会
  • Place of Presentation: 京都
  • Year and Date: 2016-11-19