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Gene therapy using genome-edited iPS cells with CD-UPRT for malignant glioma

Research Project

Project/Area Number 18K19622
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
Research InstitutionKeio University

Principal Investigator

Toda Masahiro  慶應義塾大学, 医学部(信濃町), 教授 (20217508)

Project Period (FY) 2018-06-29 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsglioblastoma / gene therapy / suicide gene / neural stem cell / CD-UPRT / migration / genome-editing / CRISPR/Cas9 / 自殺遺伝子 / iPS / 神経幹細胞 / 遺伝子治療 / 脳腫瘍
Outline of Final Research Achievements

Glioblastoma is characterized by diffuse infiltration into the normal brain. Invasive glioma stem cells (GSCs) is an underlying cause of treatment failure. Here we show that neural stem cells (NSCs) derived from CRISRP/Cas9-edited human induced pluripotent stem cell (hiPSC) expressing a suicide gene had high tumor-trophic migratory capacity, leading to marked in vivo anti-tumor effects. Time-lapse imaging of organotypic brain slice cultures first visualized the directional migration of NSCs toward GSCs and the bystander killing effect. The gene insertion to house-keeping gene locus provided higher and stable transgene expression than other common insertion sites. Our results indicate the potential benefit of NSC-based gene therapy for invasive GSCs. Furthermore, the present research concept may become a platform to promote clinical studies using hiPSC.

Academic Significance and Societal Importance of the Research Achievements

BTSCは正常脳組織へ浸潤して発育するため、既存の治療法とは異なる細胞傷害機序を有する新たな治療法の開発が望まれている。本研究の斬新性は、NSCの脳腫瘍へ集積する性質に着目し、iPS細胞から分化誘導されたNSCをBTSC治療のための遺伝子搭載細胞として利用することにある。iPS研究は再生医療への応用が急速に進められているが、脳腫瘍治療への応用はほとんどない。さらに、最新のゲノム編集技術を用いて、自殺遺伝子CD-UPRTをiPS細胞に組み込む点も意義深い。本研究手法は今後の遺伝子治療のプラットフォーム技術となる革新性を有している。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (20 results)

All 2021 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 12 results,  Open Access: 10 results) Presentation (6 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Gene Therapy Using Neural Stem/Progenitor Cells Derived from Human Induced Pluripotent Stem Cells: Visualization of Migration and Bystander Killing Effect.2020

    • Author(s)
      Tamura R, Miyoshi H, Morimoto Y, Oishi Y, Sampetrean O, Iwasawa C, Mine Y, Saya H, Yoshida K, Okano H, Toda M.
    • Journal Title

      Hum Gene Ther.

      Volume: 31(5-6) Issue: 5-6 Pages: 352-366

    • DOI

      10.1089/hum.2019.326

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Historic Overview of Genetic Engineering Technologies for Human Gene Therapy2020

    • Author(s)
      Tamura Ryota、Toda Masahiro
    • Journal Title

      Neurologia medico-chirurgica

      Volume: 60 Issue: 10 Pages: 483-491

    • DOI

      10.2176/nmc.ra.2020-0049

    • NAID

      130007926357

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Recent progress in the research of suicide gene therapy for malignant glioma.2019

    • Author(s)
      Tamura R, Miyoshi H, Yoshida K, Okano H, Toda M.
    • Journal Title

      Neurosurg Rev.

      Volume: - Issue: 1 Pages: 29-49

    • DOI

      10.1007/s10143-019-01203-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Predictive markers for MGMT promoter methylation in glioblastomas.2019

    • Author(s)
      Kanazawa T, Minami Y, Jinzaki M, Toda M, Yoshida K, Sasaki H.
    • Journal Title

      Neurosurgical Review

      Volume: - Issue: 4 Pages: 867-876

    • DOI

      10.1007/s10143-018-01061-5

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Increased Cytotoxicity of Herpes Simplex Virus Thymidine Kinase Expression in Human Induced Pluripotent Stem Cells2019

    • Author(s)
      Iwasawa Chizuru、Tamura Ryota、Sugiura Yuki、Suzuki Sadafumi、Kuzumaki Naoko、Narita Minoru、Suematsu Makoto、Nakamura Masaya、Yoshida Kazunari、Toda Masahiro、Okano Hideyuki、Miyoshi Hiroyuki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 4 Pages: 810-810

    • DOI

      10.3390/ijms20040810

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma2019

    • Author(s)
      Kikuchi Ryogo、Ueda Ryo、Saito Katsuya、Shibao Shunsuke、Nagashima Hideaki、Tamura Ryota、Morimoto Yukina、Sasaki Hikaru、Noji Shinobu、Kawakami Yutaka、Yoshida Kazunari、Toda Masahiro
    • Journal Title

      Journal of Clinical Medicine

      Volume: 8 Issue: 2 Pages: 263-263

    • DOI

      10.3390/jcm8020263

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PITX2 Expression in Non-functional Pituitary Neuroendocrine Tumor with Cavernous Sinus Invasion.2019

    • Author(s)
      Tamura R, Ohara K, Morimoto Y, Kosugi K, Oishi Y, Sato M, Yoshida K, Toda M
    • Journal Title

      Endocrine pathology

      Volume: - Issue: 2 Pages: 81-89

    • DOI

      10.1007/s12022-019-9573-8

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bridging vein and tentorial sinus in the subtemporal corridor during the anterior transpetrosal approach.2019

    • Author(s)
      Shibao S, Toda M, Fujiwara H, Jinzaki M, Yoshida K
    • Journal Title

      Acta Neurochirurgica

      Volume: 161 Issue: 4 Pages: 821-829

    • DOI

      10.1007/s00701-019-03857-w

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Difference in immunosuppressive cells between the peritumoral area and tumor core in glioblastoma.2018

    • Author(s)
      Tamura R, Ohara K, Sasaki H, Morimoto Y, Kosugi K, Yoshida K, Toda M
    • Journal Title

      World Neurosurgery

      Volume: 120 Pages: 601-610

    • DOI

      10.1016/j.wneu.2018.08.133

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Preoperative prediction of solitary fibrous tumor/hemangiopericytoma and angiomatous meningioma using magnetic resonance imaging texture analysis.2018

    • Author(s)
      Kanazawa T, Minami Y, Jinzaki M, Toda M, Yoshida K, Sasaki H
    • Journal Title

      World Neurosurgery

      Volume: 120 Pages: 1208-1216

    • DOI

      10.1016/j.wneu.2018.09.044

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment Strategy for Tuberculum Sellae Meningiomas Based on a Preoperative Radiological Assessment2018

    • Author(s)
      Kuga Daisuke、Toda Masahiro、Yoshida Kazunari
    • Journal Title

      World Neurosurgery

      Volume: 120 Pages: 1279-1288

    • DOI

      10.1016/j.wneu.2018.09.054

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Skull base venous anatomy associated with endoscopic skull base neurosurgery: a literature review2018

    • Author(s)
      Mizutani K, Akiyama T, Yoshida K, Toda M
    • Journal Title

      World Neurosurgery

      Volume: 120 Pages: 405-414

    • DOI

      10.1016/j.wneu.2018.09.067

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endoscopic endonasal approach combined with a simultaneous transcranial approach for giant pituitary tumors.2018

    • Author(s)
      Kuga D, Toda M, Ozawa H, Ogawa K, Yoshida K
    • Journal Title

      World Neurosurgery

      Volume: 121 Pages: 173-179

    • DOI

      10.1016/j.wneu.2018.10.047

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] ゲノム編集iPS細胞を用いた悪性神経膠腫に対する遺伝子細胞療法の開発2021

    • Author(s)
      戸田正博
    • Organizer
      第20回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Suicide gene therapy for malignant glioma using genome-edited human induced pluripotent stem cells2019

    • Author(s)
      田村亮太、三好浩之、森本佑紀奈、佐藤瑞仁、サンペトラ・オルテア、佐谷秀行、吉田一成、岡野栄之、戸田正博
    • Organizer
      第37回日本脳腫瘍学会
    • Related Report
      2019 Research-status Report
  • [Presentation] CD-UPRT自殺遺伝子・ゲノム編集iPS細胞を用いた悪性神経膠腫に対する治療法の開発2019

    • Author(s)
      田村亮太、三好浩之、森本佑紀奈、佐藤瑞仁、サンペトラ・オルテア、佐谷秀行、吉田一成、岡野栄之、戸田正博
    • Organizer
      第78回 日本脳神経外科学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Suicide gene therapy for malignant glioma using genome-edited human induced pluripotent stem cells2019

    • Author(s)
      戸田正博、田村亮太、三好浩之、森本佑紀奈、サンペトラ・オルテア、佐谷秀行、岡野栄之、吉田一成
    • Organizer
      第25回 日本遺伝子細胞治療学会
    • Related Report
      2019 Research-status Report
  • [Presentation] ゲノム編集iPS細胞を用いた悪性神経膠腫に対する革新的遺伝子細胞療法の開発2019

    • Author(s)
      戸田正博、田村亮太、三好浩之、岡野栄之、吉田一成
    • Organizer
      第78回 日本脳神経外科学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] ゲノム編集iPS細胞を用いた悪性神経膠腫に対する自殺遺伝子治療2018

    • Author(s)
      田村亮太、戸田正博、三好浩之、岩澤千鶴、森本佑紀奈、オルテア サンペトラ、佐谷秀行、岡野栄之、吉田一成
    • Organizer
      第36回日本脳腫瘍学会学術集会
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] ゲノム編集多能性幹細胞を用いた治療薬2020

    • Inventor(s)
      戸田正博、岡野栄之、田村亮太、佐藤瑞仁
    • Industrial Property Rights Holder
      戸田正博、岡野栄之、田村亮太、佐藤瑞仁
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2020-063477
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report 2019 Research-status Report

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Published: 2018-07-25   Modified: 2022-01-27  

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