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Elucidation of individual variation of the responsiveness to therapy for spinal muscular atrophy using a large number of disease-specific iPS cells

Research Project

Project/Area Number 19K08360
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
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, 再生医療研究室長/療養診療部長 (30420350)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords疾患モデル / iPS細胞 / 薬剤反応性 / 治療薬開発 / 創薬
Outline of Research at the Start

申請者はこれまでに、脊髄性筋萎縮症(SMA)の患者から疾患特異的人工多能性幹細胞(iPS細胞)を樹立し、その患者iPS細胞由来の神経細胞を用いて、試験管内でその病態を模倣し、各種薬剤の効果を確認することに成功した。さらに、背景の異なる多数のSMA患者のiPS細胞を樹立するとともに、ルフィナミドやラモトリギンがⅡ型やⅢ型、ビガバトリン塩酸塩がⅠ型の患者のSMN遺伝子の発現を上昇させることも見出した。本研究では、これらの研究成果をさらに発展させて、遺伝的背景や臨床的背景の異なる多数のSMA患者のiPS細胞由来の神経細胞を用いて、薬剤応答性の個人差の要因を解明する。

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 confirmed the therapeutic efficiency 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。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (4 results)

All 2022 2019

All Journal Article (4 results) (of which Peer Reviewed: 4 results,  Open Access: 4 results)

  • [Journal Article] Duchenne muscular dystrophy diagnosis using fibroblast-derived myotube cells.2022

    • Author(s)
      Okada Y, Funato M, Takeda S, Kaneko H.
    • Journal Title

      Pediatr Int.

      Volume: 64 Issue: 1

    • DOI

      10.1111/ped.15151

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Impairment of oligodendrocyte lineages in Spinal Muscular Atrophy Model Systems2019

    • 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

    • Related Report
      2019 Research-status Report
    • 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

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems2019

    • 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

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2019-04-18   Modified: 2023-01-30  

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