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Functional study for CLK-dependent pseudo exon in genetic diseases

Research Project

Project/Area Number 19K07367
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionKyoto University

Principal Investigator

Ajiro Masahiko  京都大学, 医学研究科, 特定講師 (60761864)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsRNAスプライシング / 癌免疫 / 遺伝病 / 病原性スプライシング / RNAバイオロジー / スプライシング抗原 / スプライシング変異 / 疾患モデル動物 / 低分子化合物 / アンチセンス核酸薬 / 偽エクソン / がん / 嚢胞性線維症 / 家族性自律神経異常症 / CLK阻害剤 / 人工知能 / スプライシング / SRSF / 深部イントロン / CLK / 選択的スプライシング
Outline of Research at the Start

遺伝性疾病の一部は特定遺伝子のRNAスプライシング異常に起因する。これまでの解析から深部イントロン性変異に起因する偽エクソン以上の一部がcdc-like kinase (CLK)を介した共通のメカニズムにより制御されることが明らかになった。本研究課題ではそれら偽エクソン性疾患の細胞モデル、動物モデルを用いた解析からその制御形態の詳細を解き明かすとともに治療標的としての可能性を検討する。

Outline of Final Research Achievements

RNA splicing is a fundamental process during gene expression to produce a proteome diversity, and its impairment is associated with numerous diseases. In this project, we conducted functional studies regarding disease-associated RNA splicing events, primarily focusing on those regulated by an alternative splicing factor, serine/arginine-rich splicing factor (SRSF), and upstream kinase, CDC-like kinase (CLK). We uncovered regulatory mechanisms and therapeutic manipulations for pathogenic aberrant RNA splicing in genetic diseases and cancer. We also indicated potential manipulation of cancer immunity through a specific RNA splicing regulation. Overall, outcomes from this project suggests a new direction toward RNA splicing-targeted therapeutics.

Academic Significance and Societal Importance of the Research Achievements

スプライシング制御異常と関連する疾患は数多く報告されている。しかし、個々のスプライシング異常に関する制御因子は多くの場合解明されていない。本研究課題では、個々の制御メカニズムを理解することで、アンチセンス核酸や低分子化合物による新規の治療介入の可能性を示した。また、科学的知見が特に少ない深部イントロン領域のスプライシング変異について制御機構を示すとともに、新規のスプライシング変異に関しても報告を行った。これらの研究成果は、病的スプライシング制御の理解という学術的意義、そして診断・治療への貢献という社会的意義を有する。

Report

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

    (57 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (6 results) Journal Article (9 results) (of which Int'l Joint Research: 5 results,  Open Access: 5 results,  Peer Reviewed: 6 results) Presentation (32 results) (of which Int'l Joint Research: 3 results,  Invited: 7 results) Book (1 results) Remarks (5 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] Cold Spring Harbor Laboratory/Sloan Kettering Institute(米国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] University of the West of England/University of Bristol(英国)

    • Related Report
      2020 Research-status Report
  • [Int'l Joint Research] ロックフェラー大学/コールドスプリングハーバー研究所/国立衛生研究所(米国)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] University of Southern Denmark(デンマーク)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Charles University in Prague(チェコ)

    • Related Report
      2019 Research-status Report
  • [Int'l Joint Research] Taipei Veteran's General Hospital(その他の国・地域)

    • Related Report
      2019 Research-status Report
  • [Journal Article] Switching of OAS1 splicing isoforms mitigates SARS-CoV-2 infection2021

    • Author(s)
      Iida Kei、Ajiro Masahiko、Muramoto Yukiko、Takenaga Toru、Denawa Masatsugu、Kurosawa Ryo、Noda Takeshi、Hagiwara Masatoshi
    • Journal Title

      BioRXiv

      Volume: -

    • DOI

      10.1101/2021.08.23.457314

    • Related Report
      2021 Annual Research Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia2021

    • Author(s)
      Ajiro Masahiko、Awaya Tomonari、Kim Young Jin、Iida Kei、Denawa Masatsugu、Tanaka Nobuo、Kurosawa Ryo、Matsushima Shingo、Shibata Saiko、Sakamoto Tetsunori、Studer Lorenz、Krainer Adrian R.、Hagiwara Masatoshi
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 4507-4507

    • DOI

      10.1038/s41467-021-24705-5

    • NAID

      120007141965

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CDC2-like (CLK) protein kinase inhibition as a novel targeted therapeutic strategy in prostate cancer2021

    • Author(s)
      Simon Uzor, Sean R Porazinski, Ling Li, Bethany Clark, Masahiko Ajiro, Kei Iida, Masatoshi Hagiwara, Abdullah A Alqasem, Claire M Perks, Ian D Wilson, Sebastian Oltean, and Michael R Ladomery
    • Journal Title

      Scientific Reports

      Volume: 11(1) Issue: 1 Pages: 7963-7963

    • DOI

      10.1038/s41598-021-86908-6

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia2021

    • Author(s)
      Masahiko Ajiro, Tomonari Awaya, Young Jin Kim, Kei Iida, Masatsugu Denawa, Nobuo Tanaka, Ryo Kurosawa, Shingo Matsushima, Saiko Shibata, Tetsunori Sakamoto, Rolenz Studer, Adrian R. Krainer, and Masatoshi Hagiwara
    • Journal Title

      Nature Communications

      Volume: in press

    • NAID

      120007141965

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mechanism-Based Personalized Medicine for Cystic Fibrosis by Suppressing Pseudo Exon Inclusion2020

    • Author(s)
      Saiko Shibata, Masahiko Ajiro (#), and Masatoshi Hagiwara (#)
    • Journal Title

      Cell Chemical Biology

      Volume: 27(12) Issue: 12 Pages: 1472-1482

    • DOI

      10.1016/j.chembiol.2020.08.013

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] RNAスプライシング異常を標的とした創薬展開/Drug Development by Targeting Aberrant RNA Splicing2020

    • Author(s)
      網代将彦、萩原正敏
    • Journal Title

      Medical Science Digest

      Volume: 46(9) Pages: 550-554

    • Related Report
      2020 Research-status Report
  • [Journal Article] Oncogenic splicing factor SRSF3 regulates ILF3 alternative splicing to promote cancer cell proliferation and transformation2019

    • Author(s)
      Rong Jia, Masahiko Ajiro, Lulu Yu, Philip McCoy Jr. and Zhi-Ming Zheng
    • Journal Title

      RNA

      Volume: 25 Issue: 5 Pages: 630-644

    • DOI

      10.1261/rna.068619.118

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] ―スプライシング応答の可視化― スプライシング変異から挑むプレシジョンメディシン2019

    • Author(s)
      網代将彦
    • Journal Title

      Precission Medicine

      Volume: 2 Pages: 483-486

    • Related Report
      2019 Research-status Report
  • [Journal Article] Rescue of recurrent deep intronic mutation underlying cell type-dependent quantitative NEMO deficiency2018

    • Author(s)
      Boisson Bertrand、Honda Yoshitaka、Ajiro Masahiko、Bustamante Jacinta、Bendavid Matthieu、Gennery Andrew R.、Kawasaki Yuri、Ichishima Jose、Osawa Mitsujiro、Nihira Hiroshi、Shiba Takeshi、Tanaka Takayuki、Chrabieh Maya、Bigio Benedetta、Hur Hong、Itan Yuval、Liang Yupu、Okada Satoshi、et al.
    • Journal Title

      Journal of Clinical Investigation

      Volume: 129 Issue: 2 Pages: 583-597

    • DOI

      10.1172/jci124011

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] スプライシング標的化合物による筋疾患治療への挑戦2021

    • Author(s)
      網代将彦、粟屋智就、萩原正敏
    • Organizer
      第7回 日本筋学会学術集会 シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia2021

    • Author(s)
      Masahiko Ajiro, Kei Iida, Tomonari Awaya, Krainer Adrian, Masatoshi Hagiwara
    • Organizer
      第44回 日本分子生物学会年会ワークショップ
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Boosted tumor immunogenicity by splicing modulation potentiates the response to immune checkpoint therapy2021

    • Author(s)
      Shingo Matsushima, Masahiko Ajiro, Kenji Chamoto, Tasuku Honjo, Masatoshi Hagiwara
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Precision Medicine to Provide Resistance to SARS-CoV-2 Infection by Switching OAS1 Splicing Isoforms2021

    • Author(s)
      Kei Iida, Masahiko Ajiro, Yukiko Muramoto, Toru Takenaga, Masatsugu Denawa, Ryo Kurosawa, Takeshi Noda, Masatoshi Hagiwara
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Comprehensive analysis of whole-genome sequence for deep-intronic splicing-associated variant2021

    • Author(s)
      Ryo Kurosawa, Masahiko Ajiro, Kei Iida, Masatoshi Hagiwara
    • Organizer
      第44回 日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia2021

    • Author(s)
      Masahiko Ajiro, Kei Iida, Tomonari Awaya, Krainer R. Adrian, and Masatoshi Hagiwara
    • Organizer
      第22回日本RNA学会年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Precision Medicine to Provide Resistance to SARS-CoV-2 Infection by Switching OAS1 Splicing Isoforms2021

    • Author(s)
      Kei Iida, Masahiko Ajiro, Yukiko Muramoto, Toru Takenaga, Masatsugu Denawa, Ryo Kurosawa, Takeshi Noda, and Masatoshi Hagiwara
    • Organizer
      Cold Spring Harbor Laboratory Eukaryotic mRNA Processing Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A synonymous SCN5A variant p.E446E causing Brugada Syndrome via cryptic donor site splicing2021

    • Author(s)
      Yuichi Sawayama, Koichi Kato, Masahiko Ajiro, Ryo Kurosawa, Seiko Ohno, Yoshihisa Nakagawa, Minoru Horie
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 先天性QT延長症候群I型に対するスプライシング制御化合物の検討2021

    • Author(s)
      牧ケ谷佳佑、牧山武、網代将彦、萩原正敏
    • Organizer
      第7回 日本筋学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 病原性深部イントロン変異の検出に向けたスクリーニング手法の検討2021

    • Author(s)
      黒澤凌、網代将彦、飯田慶、粟屋智就、萩原正敏
    • Organizer
      第7回 日本筋学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia2021

    • Author(s)
      Masahiko Ajiro, Kei Iida, Tomonari Awaya, Krainer R. Adrian, and Masatoshi Hagiwara
    • Organizer
      Cold Spring Harbor Laboratory Eukaryotic mRNA Processing Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Genome-wide Screening for Pseudo-exonic Variants and their Modulation by CLK Inhibitors2021

    • Author(s)
      黒澤凌、網代将彦、萩原正敏
    • Organizer
      京都大学医薬系研究交流サロン
    • Related Report
      2021 Annual Research Report
  • [Presentation] New strategy for enhancing tumor immunity by splicing modulator-mediated splice-neoantigens2021

    • Author(s)
      Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, and Masatoshi Hagiwara
    • Organizer
      京都大学 発生細胞生物学システム生物学リトリート
    • Related Report
      2021 Annual Research Report
  • [Presentation] Amending splicing defects by small molecule compounds/低分子化合物による病原性スプライシングの制御2020

    • Author(s)
      Masahiko Ajiro, Masatoshi Hagiwara
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] A synonymous SCN5A variant p.E446E causing Brugada Syndrome via cryptic donor site splicing2020

    • Author(s)
      Yuichi Sawayama, Koichi Kato, Masahiko Ajiro, Ryo Kurosawa, Seiko Ohno, Yoshihisa Nakagawa, Minoru Horie
    • Organizer
      第85回日本循環器学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Genome-wide Screening for Pseudo-exonic Variants and their Modulation by CLK Inhibitors2020

    • Author(s)
      黒澤凌、網代将彦、萩原正敏
    • Organizer
      京都大学メディカルイノベーション卓越大学院プログラム・医薬系研究交流サロン
    • Related Report
      2020 Research-status Report
  • [Presentation] スプライシング治療薬による遺伝病治療の試み2020

    • Author(s)
      萩原正敏、伊藤慎二、網代将彦
    • Organizer
      第45回日本医用マススペクトル学会年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] CLK-SRSF経路の阻害による偽エクソン型スプライシング疾患の治療効果2020

    • Author(s)
      網代将彦
    • Organizer
      第21回 日本RNA学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] New strategy for enhancing tumor immunity by splicing modulator-mediated splice-neoantigens.2020

    • Author(s)
      Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, and Masatoshi Hagiwara
    • Organizer
      京都大学 発生細胞生物学システム生物学リトリート
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 偽エクソン型スプライス変異の探索と化合物応答性評価/Investigation of pathogenic pseudo exons and their amendment by small molecules.2020

    • Author(s)
      黒澤凌、網代将彦、萩原正敏
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 心ファブリー病に対するスプライシング制御化合物に関する研究開発2020

    • Author(s)
      網代将彦、粟屋智就、田中信生、萩原正敏
    • Organizer
      国立研究開発法人日本医療研究開発機構 2事業合同成果報告会「疾患克服への挑戦2019」
    • Related Report
      2020 Research-status Report
  • [Presentation] Application of Splice-Targeting Small Molecule Compounds for Pathogenic Pseudo Exons Caused by Deep-Intronic Mutations. 病原性深部イントロン変異に起因する偽エクソンを標的としたスプライシング制御化合物の検討2020

    • Author(s)
      網代将彦、本田吉孝、八角高裕、萩原正敏
    • Organizer
      京都大学メディカルイノベーション卓越大学院プログラム・医薬系研究交流サロン
    • Related Report
      2020 Research-status Report
  • [Presentation] CLK-SRSF経路の阻害による偽エクソン型スプライシング疾患の治療効果2019

    • Author(s)
      網代将彦
    • Organizer
      第21回 日本RNA学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 心ファブリー病に対するスプライシング制御化合物に関する研究開発2019

    • Author(s)
      網代将彦、粟屋智就、田中信生、萩原正敏
    • Organizer
      疾患克服への挑戦2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Application of Splice-Targeting Small Molecule Compounds for Pathogenic Pseudo Exons Caused by Deep-Intronic Mutations2019

    • Author(s)
      網代将彦、本田吉孝、八角高裕、萩原正敏
    • Organizer
      京都大学メディカルイノベーション卓越大学院プログラム・医薬系研究交流サロン
    • Related Report
      2019 Research-status Report
  • [Presentation] 深部イントロン変異に起因する偽エクソンを標的としたCLK-SRSF経路阻害効果2019

    • Author(s)
      網代将彦、本田吉孝、八角高祐、萩原正敏
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] MTRR遺伝子偽エクソン型変異に対するCLK阻害化合物の検討2019

    • Author(s)
      劉百香、網代将彦、萩原正敏
    • Organizer
      第42回 日本分子生物学会年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Oncogenic role of splicing factor SRSF3 through ILF3 and targeting SR protein function by CLK inhibitor.2019

    • Author(s)
      網代将彦、萩原正敏
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Therapeutic effect of CLK inhibition for EDA-ID caused by the IVS4+866 C>T deep-intronic mutation of NEMO gene.2019

    • Author(s)
      Masahiko Ajiro, Yoshitaka Honda, Jean Laurent Casanova, Takahiro Yasumi, and Masatoshi Hagiwara.
    • Organizer
      Cold Spring Harbor Laboratory eukaryotic mRNA processing meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] NEMO異常症の偽エクソン型変異に対するCLKを標的とした治療戦略2019

    • Author(s)
      網代将彦、本田吉孝、八角高祐、萩原正敏
    • Organizer
      第14回 日本ケミカルバイオロジー学会
    • Related Report
      2019 Research-status Report
  • [Presentation] スプライシング異常を原因とする嚢胞性線維症に対する低分子治療薬の探索2019

    • Author(s)
      柴田済子、網代将彦、萩原正敏
    • Organizer
      第14回 日本ケミカルバイオロジー学会
    • Related Report
      2019 Research-status Report
  • [Presentation] Assessment of antiviral effect of FIT-039 against Kaposi’s sarcoma-associated herpesvirus.2019

    • Author(s)
      Tetsunori Sakamoto, Masahiko Ajiro, Keiji Ueda, and Masatoshi Hagiwara
    • Organizer
      世界をリードする次世代MD研究者・養成プロジェクト2019年度全国リトリート
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] スプライシング疾患の低分子創薬に向けて―家族性自律神経失調症に対する候補化合物RECTAS (Drug development targeting splicing diseases―Therapeutic potential of RECTAS for familial dysautonomia)(「医学のあゆみ」誌2022

    • Author(s)
      網代将彦、萩原正敏
    • Total Pages
      2
    • Publisher
      医歯薬出版
    • Related Report
      2021 Annual Research Report
  • [Remarks] 遺伝病を薬で治す -家族性自律神経失調症に対する低分子化合物による効果を実証-

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2021-07-28-2

    • Related Report
      2021 Annual Research Report
  • [Remarks] 嚢胞性線維症に対する新しい治療薬を発見 -スプライス制御による難病の治療-

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2020-09-09

    • Related Report
      2020 Research-status Report
  • [Remarks] 京都大学大学院 医学研究科創薬医学講座

    • URL

      http://www.mic.med.kyoto-u.ac.jp/dddm/members/ajiro.html

    • Related Report
      2020 Research-status Report
  • [Remarks] 京都大学大学院 医学研究科形態形成機構学教室

    • URL

      https://www.anat1dadb.med.kyoto-u.ac.jp/

    • Related Report
      2020 Research-status Report
  • [Remarks] 京都大学大学院 医学研究科 創薬医学講座

    • URL

      http://www.mic.med.kyoto-u.ac.jp/dddm/members/ajiro.html

    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] ウイルスを原因とする腫瘍を抑制する医薬組成物2019

    • Inventor(s)
      萩原正敏、網代将彦、阪本哲紀
    • Industrial Property Rights Holder
      萩原正敏、網代将彦、阪本哲紀
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] ヒトパピローマウイルスの排除方法2019

    • Inventor(s)
      萩原正敏、網代将彦、小野木博
    • Industrial Property Rights Holder
      萩原正敏、網代将彦、小野木博
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] アルツハイマー病のための医薬組成物2019

    • Inventor(s)
      萩原正敏、網代将彦
    • Industrial Property Rights Holder
      萩原正敏、網代将彦
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
  • [Patent(Industrial Property Rights)] PHARMACEUTICAL COMPOSITION AND TREATMENT METHOD FOR GENETIC DISEASE ASSOCIATED WITH SPLICING ABNORMALITIES2019

    • Inventor(s)
      萩原正敏、網代将彦
    • Industrial Property Rights Holder
      萩原正敏、網代将彦
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Research-status Report
    • Overseas

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

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