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Functional evaluation of iPSC-derived cardiomyocytes in DMD patients by exon skip therapy

Research Project

Project/Area Number 18K15026
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionNational Center of Neurology and Psychiatry (2019)
Shinshu University (2018)

Principal Investigator

Sato Mitsuto  国立研究開発法人国立精神・神経医療研究センター, 神経研究所 遺伝子疾患治療研究部, 流動研究員 (10816630)

Project Period (FY) 2018-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsデュシェンヌ型筋ジストロフィー / 心筋 / アンチセンス核酸医薬 / エクソン・スキップ治療 / カルシウムイメージング / エクソンスキップ / iPSC / Duchenne型筋ジストロフィー / 心筋細胞 / iPS細胞
Outline of Final Research Achievements

We established induced-pluripotent stem cells (iPSCs) from T cells from a DMD patient carrying a DMD-exon 46e55 deletion, differentiated the iPSCs into cardiomyocytes, and treated them with phosphorodiamidate morpholino oligomers. The efficiency of exon-45 skipping increased in a dose-dependent manner and enabled restoration of the DMD gene product, dystrophin. Further, Ca2+ imaging analysis showed a decreased number of arrhythmic cells and improved transient Ca2+ signaling after exon skipping. Thus, the restoration of dystrophin expression may improve Ca2 + kinetics in DMD cardiomyocytes.

Academic Significance and Societal Importance of the Research Achievements

DMD遺伝子エクソン46-55欠失DMD患者iPS細胞由来心筋細胞において、PMOを用いたエクソン45スキップにより、エクソン45-55欠失型に変換されてジストロフィンが回復し、心筋細胞の筋小胞体におけるカルシウム動態が改善することが示唆された。筋小胞体が関与した細胞内カルシウム濃度上昇は心室性不整脈の原因となることが報告されており、ジストロフィン回復によりそれらの致死性不整脈発生の抑制効果が期待される。本研究結果はDMD患者の約60%が変異を有するエクソン45-55領域をターゲットとしたマルチエクソン・スキッピング治療が、DMDの心筋障害に対しても有用である可能性を示唆している。

Report

(3 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • Research Products

    (3 results)

All 2019 2018

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results)

  • [Journal Article] Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes.2019

    • Author(s)
      Sato M, Shiba N, Miyazaki D, Shiba Y, Echigoya Y, Yokota T, Takizawa H, Aoki Y, Takeda S, Nakamura A.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 520 Issue: 1 Pages: 179-185

    • DOI

      10.1016/j.bbrc.2019.09.095

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] DMD遺伝子exon46-55欠失変異を持つDMD患者iPSC由来心筋細胞に対するexon 45 skip治療に関する研究2019

    • Author(s)
      佐藤 充人
    • Organizer
      第5回 日本筋学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Exon 45 skipping therapy of iPS cells from a DMD patient with exon 46-55 deletion.2018

    • Author(s)
      佐藤 充人
    • Organizer
      第59回 日本神経学会学術大会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2021-02-19  

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