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Restoration of inner ear gap junction with iPS derived model cell and genome editing

Research Project

Project/Area Number 17H04348
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Otorhinolaryngology
Research InstitutionJuntendo University

Principal Investigator

Ikeda Katsuhisa  順天堂大学, 医学部, 教授 (70159614)

Co-Investigator(Kenkyū-buntansha) 美野輪 治  順天堂大学, 医学部, 准教授 (00181967)
井下 綾子  順天堂大学, 医学部, 准教授 (00514762)
神谷 和作  順天堂大学, 医学部, 准教授 (10374159)
安齋 崇  順天堂大学, 医学部, 助教 (20624852)
赤松 和土  順天堂大学, 医学(系)研究科(研究院), 教授 (60338184)
飯塚 崇  順天堂大学, 医学部, 非常勤助教 (40372932)
城所 淑信  順天堂大学, 医学部, 助手 (60514487)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords遺伝性難聴 / iPS細胞 / ギャップ結合 / GJB2 / ゲノム編集 / 内耳 / 遺伝子改変動物
Outline of Final Research Achievements

Mutation of the Gap Junction Beta 2 gene (GJB2) is the most frequent cause of hereditary deafness worldwide and accounts for up to 50% of non-syndromic sensorineural hearing loss. In this study, we examined various adeno associated virus (AAV) serotypes to develop the effective gene therapy for GJB2 related hearing loss. For the disease modeling, we developed a novel strategy to differentiate induced pluripotent stem (iPS) cells into functional CX26-GJP-forming cells that exhibit physiological properties typical of the developing cochlea. To establish the disease model cells from the patients, we generated human iPS cells from the patients with Japanese and East Asian typical GJB2 mutations. As animal models for these typical GJB2 mutations, CRSPR/Cas9 based genome editing were used to establish the mouse model such as GJB2-V37I mutant mouse. These model cells, vectors and animal models will enable us to develop the drugs and gene therapy vectors for GJB2 related hearing loss.

Academic Significance and Societal Importance of the Research Achievements

本課題はこれまでの当グループの研究成果をさらに発展させ、新たな疾患モデル細胞、疾患モデル動物、遺伝子治療ベクター等を開発することにより、根本的治療の存在しなかった遺伝性難聴への遺伝子治療と細胞治療が応用可能であることを示す結果が得られた。ギャップ結合の障害は加齢性難聴の進行に関与することが我々の論文で示されたが、加齢性難聴は認知症のリスクファクターとして最も重要な疾患であることが近年明らかとなり、本課題の成果が認知症分野へも貢献する社会的意義の高い治療法開発であると考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (12 results)

All 2020 2019 2018 2017

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (1 results) (of which Invited: 1 results)

  • [Journal Article] Degradation and modification of cochlear gap junction proteins in the early development of age-related hearing loss.2020

    • Author(s)
      Tajima S, Danzaki K, Ikeda K, Kamiya K.
    • Journal Title

      Experimental and Molecular Medicine

      Volume: 52 Pages: 166-175

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Generation of the induced pluripotent stem cell (hiPSC) line (JUFMDOi004-A) from a patient with hearing loss carrying GJB2 (p.V37I) mutation.2020

    • Author(s)
      Fukunaga I, Shiga T, Chen C, Oe Y, Danzaki K, Ohta S, Matsuoka R, Anzai T, Hibiya-Motegi R, Tajima S, Ikeda K, Akamatsu W, Kamiya K.
    • Journal Title

      Stem Cell Research

      Volume: 4

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Generation of Functional CX26-Gap-Junction-Plaque-Forming Cells with Spontaneous Ca2+ Transients via a Gap Junction Characteristic of Developing Cochlea.2019

    • Author(s)
      Fukunaga I, Fujimoto A, Hatakeyama K, Kurebayashi N, Ikeda K, Kamiya K.
    • Journal Title

      Current Protocols in Stem Cell Biology

      Volume: 51

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Postoperative Management of Eosinophilic Chronic Rhinosinusitis with Nasal Polyps: Impact of High-Dose Corticosteroid Nasal Spray.2019

    • Author(s)
      Ikeda K, Ito S, Hibiya R, Homma H, Ono N, Okada H, Kidokoro Y, Shiozawa A, Kusunoki T.
    • Journal Title

      Int Arch Otorhinolaryngol

      Volume: 23 Issue: 01 Pages: 101-103

    • DOI

      10.1055/s-0038-1668515

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of inhibitory mechanisms in pseudo-allergy involving Mrgprb2/MRGPRX2-mediated mast cell activation2019

    • Author(s)
      Takamori A, Ozawa K, Kaitani A, Ando T, Okamoto Y, Maehara A, Tanabe A, Nagamine M, Yamada H, Uchida S, Uchida K, Isobe M, Hatayama T, Watanabe D, Ando T, Ide T, Matsuzawa M, Maeda K, Nakano N, Tamura N, Ikeda K, Ebihara N, Shimizu T, Ogawa H, Okumura K, Kitaura J
    • Journal Title

      Journal of Allergy and Clinical Immunology

      Volume: 143 Issue: 3 Pages: 1231-1235

    • DOI

      10.1016/j.jaci.2018.10.034

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Age-stratified sex differences in polysomnographic findings and pharyngeal morphology among children with obstructive sleep apnea2018

    • Author(s)
      Inoshita Ayako、Kasai Takatoshi、Matsuoka Rina、Sata Naoko、Shiroshita Nanako、Kawana Fusae、Kato Mitsue、Ikeda Katsuhisa
    • Journal Title

      Journal of Thoracic Disease

      Volume: 10 Issue: 12 Pages: 6702-6710

    • DOI

      10.21037/jtd.2018.11.09

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Are human ATP-binding cassette transporter C11 and earwax associated with the incidence of cholesteatoma?2018

    • Author(s)
      Nakagawa Hiroshi、Toyoda Yu、Albrecht Tobias、Tsukamoto Megumi、Praetorius Mark、Ishikawa Toshihisa、Kamiya Kazusaku、Kusunoki Takeshi、Ikeda Katsuhisa、Sertel Serkan
    • Journal Title

      Med. Hypotheses

      Volume: 114 Pages: 19-22

    • DOI

      10.1016/j.mehy.2018.02.030

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A case of ectopic salivary gland of the larynx.2018

    • Author(s)
      Tajima S, Yamauchi K, Higo R, Ikeda K.
    • Journal Title

      Auris Nasus Larynx

      Volume: 45 Issue: 3 Pages: 633-636

    • DOI

      10.1016/j.anl.2017.08.001

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 内耳と免疫-内耳基礎研究の新展開を求めて- 内耳ケモカイン発現を応用した内耳組織への多能性幹細胞誘導法の開発2018

    • Author(s)
      神谷 和作
    • Journal Title

      耳鼻咽喉科免疫アレルギー

      Volume: 36 Pages: 65-65

    • Related Report
      2018 Annual Research Report
  • [Journal Article] 蝸牛ギャップ結合を標的とした遺伝性難聴の創薬と治療法の開発2018

    • Author(s)
      神谷 和作
    • Journal Title

      Otology Japan

      Volume: 28 Pages: 79-81

    • NAID

      130007606364

    • Related Report
      2018 Annual Research Report
  • [Journal Article] A Case of Glomangiopericytoma at the Nasal Septum.2017

    • Author(s)
      Takashi Anzai, Tsuyoshi Saito, Miri Toh, Katsuhisa Ikeda, Shin Ito
    • Journal Title

      Head and Neck Pathology

      Volume: - Issue: 4 Pages: 572-575

    • DOI

      10.1007/s12105-017-0870-6

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 内耳ギャップジャンクションを標的としたiPS細胞からの遺伝性難聴モデル細胞と内耳細胞治療法の開発2017

    • Author(s)
      神谷和作
    • Organizer
      日本分子生物学会
    • Related Report
      2017 Annual Research Report
    • Invited

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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