Establishment of a multi-lineage model of infantile Pompe disease using patient-derived iPS cells

• Project/Area Number: 17K16253
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: Yoshida Takeshi 京都大学, 医学研究科, 助教 (50790557)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Pompe病 / iPS細胞 / 疾患モデル / 神経筋疾患 / 骨格筋 / 肝臓 / 糖原病 / 筋細胞分化誘導 / 肝細胞分化誘導 / 肝細胞分化 / 疾患特異的iPS細胞 / 骨格筋細胞分化誘導 / 乳児型Pompe病 / ライソゾーム

Outline of Final Research Achievements

Pompe disease (glycogen storage disese type II) is a hereditary disease, caused by a defect of a lysosomal enzyme, acid α-glucosidase, and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle, liver, and heart. In this study, we generated induced pluripotent stem cells (iPSCs) from three patients with infantile-onset Pompe disease (IOPD) and three healthy controls, and differentiated them into muscle cells and liver cells. Differentiated cells showed lysosomal glycogen accumulation, the hallmark of Pompe disease. In conclusion, we succeeded in in vitro recapitulation of both skeletal muscle and liver phenotypes of IOPD using patient-derived iPSCs. We expect our modeling system will help elucidate more details of disease mechanism or establish an efficient drug-screening platform.

Academic Significance and Societal Importance of the Research Achievements

Pompe病は筋肉（特に骨格筋）、肝臓、心臓などの臓器にグリコーゲンが蓄積する希少難病である。本研究では、Pompe病患者から作成したiPS細胞を用いて、筋肉と肝臓での病態を実験室レベルで再現することに成功した。このiPS細胞由来病態モデルを利用することで、これまでにない新しい薬剤の発見や、臓器別の病態解明が期待できる。Pompe病以外の様々な希少難病にも応用可能なアプローチであり、希少難病研究の発展にも寄与することも期待できる。

Research Products

• [Journal Article] A Liver Model of Infantile-Onset Pompe Disease Using Patient-Specific Induced Pluripotent Stem Cells (2019)
  • Author(s): Yoshida Takeshi、Jonouchi Tatsuya、Osafune Kenji、Takita Junko、Sakurai Hidetoshi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 7
  • DOI: 10.3389/fcell.2019.00316
  • NAID: 120006940293
  • Peer Reviewed / Open Access
• [Journal Article] A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells (2017)
  • Author(s): Takeshi Yoshida, Tomonari Awaya, Tatsuya Jonouchi, Ryo Kimura, Shigemi Kimura, Takumi Era, Toshio Heike & Hidetoshi Sakurai
  • Journal Title: Scientific Reports Volume: 7 Issue: 1
  • DOI: 10.1038/s41598-017-14063-y
  • Peer Reviewed / Open Access
• [Presentation] A skeletal muscle model of infantile-onset Pompe disease using patient-specific iPS cells (2018)
  • Author(s): Takeshi YOSHIDA, Tomonari AWAYA, Tatsuya JONOUCHI, Ryo KIMURA, Shigemi KIMURA, Takumi ERA, Kanako MAIZURU, Masatoshi NAKATA, Atsushi YOKOYAMA, Hidetoshi SAKURAI, Toshio HEIKE
  • Organizer: 第60回日本小児神経学術集会
• [Presentation] Modeling Infantile-onset Pompe Disease with Patient iPSCs Reveals Disturbed mTORC1 Signaling as an Early Pathogenesis of the Skeletal Muscle Damage (2017)
  • Author(s): Takeshi Yoshida
  • Organizer: The 14th Asian and Oceanian Congress of Child Neurology (AOCCN2017)
  • Int'l Joint Research