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Fundamental Research for an Innovative Drug Discovery Based on the Molecular Pathomechanisms of Refractory Epilepsy Using a Multidimensional Approach.

Research Project

Project/Area Number 20H03651
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionFukuoka University

Principal Investigator

Hirose Shinichi  福岡大学, 医学部, 教授 (60248515)

Co-Investigator(Kenkyū-buntansha) 荻原 郁夫  日本医科大学, 医学部, 准教授 (30373286)
石井 敦士  国際医療福祉大学, 福岡保健医療学部, 教授 (90568825)
Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2022: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2021: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Keywordsてんかん / iPS細胞 / 遺伝子改変動物 / ハイスルーブットスクリーニング / 創薬 / ハイスループットスクリーニング
Outline of Research at the Start

本研究では分子病態に基づく抗難治性てんかん薬の創薬基盤形成を多面的手法で行う。1:ヒトと動物のてんかんを引き起こす遺伝子同定とその分子ネットワークの解明。2:1の情報による遺伝子改変動物作出。3:1の対象者のiPS細胞等の幹細胞と、その遺伝子改変幹細胞の樹立。4:1の分子ネットワークに介入する薬剤・化合物を分子会合シミュレーションで選択。5:3の幹細胞由来の神経細胞を用いて4で選択の薬剤・化合物からシーズ選択。6:2で作出された動物を用いて5のシーズの有効性判定を実施する。

Outline of Final Research Achievements

In human epilepsy, numerous genetic mutations were identified, and simultaneously, genes believed to be responsible for naturally occurring epilepsy in animals were also identified. Based on this information, model animals for Dravet syndrome were created, revealing abnormalities in synaptic function and the relationship between brain development and the onset of symptoms. Furthermore, stem cells established from epilepsy patients were differentiated into neurons, elucidating their molecular pathology. Building on this, drugs and compounds capable of intervening in the pathology were explored from multiple angles. Two candidate compounds were identified, and analyses were conducted on their blood-brain barrier permeability and other properties to serve as seeds for antiepileptic drugs. Additionally, it was found that these compounds improve epilepsy symptoms and reduce mortality in genetically modified animal.

Academic Significance and Societal Importance of the Research Achievements

てんかんの遺伝子が最初に同定されたのは1995年で、2003年からは次世代シークエンスにより、多くの遺伝子が同定されるようになった。最近になって、ようやくてんかんの分子病態が明らかになってきた。このため、分子病態に基づく創薬の試みは、海外で緒に就いたばかりであり、国内で我々以外にない。加えて、多手法を用いて多目的に実施しようとするのは本研究以外に未だ見当たらない。分子病態に基づく治療が開発できれば、てんかんの根治療法となり、現在3割程度存在する難治性てんかんへの大きな光明となる。

Report

(4 results)
  • 2023 Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (38 results)

All 2023 2022 2021 2020

All Journal Article (23 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 21 results,  Open Access: 14 results) Presentation (13 results) (of which Int'l Joint Research: 5 results,  Invited: 10 results) Book (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Astrocyte Ca2+ signaling is facilitated in Scn1a+/? mouse model of Dravet syndrome2023

    • Author(s)
      Uchino Kouya、Tanaka Yasuyoshi、Ikezawa Wakana、Deshimaru Masanobu、Kubota Kaori、Watanabe Takuya、Katsurabayashi Shutaro、Iwasaki Katsunori、Hirose Shinichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 643 Pages: 169-174

    • DOI

      10.1016/j.bbrc.2022.12.084

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetics and gene therapy in Dravet syndrome.2022

    • Author(s)
      Higurashi N, Broccoli V, Hirose S.
    • Journal Title

      Epilepsy Behav.

      Volume: 131 Pages: 108043-108043

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Burden of seizures and comorbidities in patients with epilepsy: a survey based on the tertiary hospital-based Epilepsy Syndrome Registry in Japan.2022

    • Author(s)
      Inoue Y, Hamano SI, Hayashi M, Sakuma H, Hirose S, Ishii A, Honda R, Ikeda A, Imai K, Jin K, Kada A, Kakita A, Kato M, Kawai K, Kawakami T, Kobayashi K, Matsuishi T, Matsuo T, Nabatame S, Okamoto N, Ito S, Okumura A, Saito A, Shiraishi H, Shirozu H, Saito T, Sugano H, Takahashi Y, Yamamoto H, Fukuyama T, Kuki I.
    • Journal Title

      Epileptic Disord

      Volume: 24 Issue: 1 Pages: 82-94

    • DOI

      10.1684/epd.2021.1361

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The effectiveness of intravenous benzodiazepine for status epilepticus in Dravet syndrome.2022

    • Author(s)
      Kikuchi K, Hamano SI, Matsuura R, Nonoyama H, Daida A, Hirata Y, Koichihara R, Hirano D, Ishii A, Hirose S.
    • Journal Title

      Brain Dev

      Volume: 44(5) Issue: 5 Pages: 319-28

    • DOI

      10.1016/j.braindev.2022.01.004

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate2022

    • Author(s)
      Suzuki T, Tatsukawa T, Sudo G, Delandre C, Pai YJ, Miyamoto H, Raveau M, Shimohata A, Ohmori I, Hamano S, Haginoya K, Uematsu M, Takahashi Y, Morimoto M, Fujimoto S, Osaka H, Oguni H, Osawa M, Ishii A, Hirose S, Kaneko S, Inoue Y, Moore AW, Yamakawa K.
    • Journal Title

      Scientific Reports

      Volume: 12 Issue: 1 Pages: 6505-6505

    • DOI

      10.1038/s41598-022-10715-w

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutation in the STXBP1 Gene Associated with Early Onset West Syndrome: A Case Report and Literature Review2022

    • Author(s)
      Takeda Kanako、Miyamoto Yusaku、Yamamoto Hisako、Iwasaki Toshiyuki、Sumitomo Noriko、Takeshita Eri、Ishii Atsushi、Hirose Shinichi、Shimizu Naoki
    • Journal Title

      Pediatric Reports

      Volume: 14 Issue: 4 Pages: 386-395

    • DOI

      10.3390/pediatric14040046

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of autaptic culture with human-induced pluripotent stem cell-derived astrocytes2022

    • Author(s)
      Uchino Kouya、Tanaka Yasuyoshi、Kawaguchi Sayaka、Kubota Kaori、Watanabe Takuya、Katsurabayashi Shutaro、Hirose Shinichi、Iwasaki Katsunori
    • Journal Title

      iScience

      Volume: 25 Issue: 8 Pages: 104762-104762

    • DOI

      10.1016/j.isci.2022.104762

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current medico-psycho-social conditions of patients with West syndrome in Japan.2021

    • Author(s)
      Yoshitomi S, Hamano SI, Hayashi M, Sakuma H, Hirose S
    • Journal Title

      Epileptic Disord

      Volume: 23(4) Pages: 579-89

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibitory synaptic transmission is impaired at higher extracellular Ca(2+) concentrations in Scn1a(+/-) mouse model of Dravet syndrome.2021

    • Author(s)
      Uchino K, Kawano H, Tanaka Y, et.al.
    • Journal Title

      Sci Rep

      Volume: 11(1) Pages: 10634-10634

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Astrocyte Ca2+ Signaling is Facilitated in an Scn1a+/- Mouse Model of Dravet Syndrome.2021

    • Author(s)
      Uchino K, Ikezawa W, Tanaka Y, et.al.
    • Journal Title

      bioRxiv

      Volume: 05(18) Pages: 444602-444602

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PCDH19 missense and truncating variants in PCDH19-related epilepsy.2021

    • Author(s)
      Shibata M, Ishii A, Goto A, Hirose S.
    • Journal Title

      J Hum Genet.

      Volume: 66(6) Pages: 569-78

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impaired neuronal activity and differential gene expression in STXBP1 encephalopathy patient iPSC-derived GABAergic neurons.2021

    • Author(s)
      Ichise E, Chiyonobu T, Ishikawa M, et.al
    • Journal Title

      Hum Mol Genet.

      Volume: 30(14) Pages: 1337-48

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetics and gene therapy in Dravet syndrome2021

    • Author(s)
      Higurashi Norimichi、Broccoli Vania、Hirose Shinichi
    • Journal Title

      Epilepsy & Behavior

      Volume: --- Pages: 108043-108043

    • DOI

      10.1016/j.yebeh.2021.108043

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals.2021

    • Author(s)
      Epi25 Collaborative (Shinichi Hirose, Atsushi Ishii)
    • Journal Title

      Am J Hum Genet.

      Volume: 108(10) Pages: 965-982

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Clinical features of early myoclonic encephalopathy caused by a CDKL5 mutation.2020

    • Author(s)
      Takeda K, Miyamoto Y, Yamamoto H, Ishii A, Hirose S, Yamamoto H.
    • Journal Title

      Brain Dev.

      Volume: 42 Issue: 1 Pages: 73-76

    • DOI

      10.1016/j.braindev.2019.08.003

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020

    • Author(s)
      Suzuki Toshimitsu、Suzuki Toshifumi、Raveau Matthieu、Miyake Noriko、Sudo Genki、Tsurusaki Yoshinori、Watanabe Takaki、Sugaya Yuki、.....Kano Masanobu、Shimoji Takeyoshi、Matsumoto Naomichi、Yamakawa Kazuhiro
    • Journal Title

      Annals of Clinical and Translational Neurology

      Volume: 7 Issue: 7 Pages: 1117

    • DOI

      10.1002/acn3.51093

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Comparative characterization of PCDH19 missense and truncating variants in PCDH19-related epilepsy2020

    • Author(s)
      Shibata Mami、Ishii Atsushi、Goto Ayako、Hirose Shinichi
    • Journal Title

      Journal of Human Genetics

      Volume: 66 Issue: 6 Pages: 569-578

    • DOI

      10.1038/s10038-020-00880-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Case-control association study of rare nonsynonymous variants of SCN1A and KCNQ2 in acute encephalopathy with biphasic seizures and late reduced diffusion2020

    • Author(s)
      Shibata Akiko、Kasai Mariko、Terashima Hiroshi、Hoshino Ai、Miyagawa Taku、Kikuchi Kenjiro、Ishii Atsushi、Matsumoto Hiroshi、Kubota Masaya、Hirose Shinichi、Oka Akira、Mizuguchi Masashi
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 414 Pages: 116808-116808

    • DOI

      10.1016/j.jns.2020.116808

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Epigenetics explained: a topic "primer" for the epilepsy community by the ILAE Genetics/Epigenetics Task Force.2020

    • Author(s)
      Kobow K, Reid CA, van Vliet EA, Becker AJ, Carvill GL, Goldman AM, Hirose S, Lopes-Cendes I, Khiari HM, Poduri A, Johnson MR, Henshall DC.
    • Journal Title

      Epileptic Disord

      Volume: 22 Issue: 2 Pages: 127-41

    • DOI

      10.1684/epd.2020.1143

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Establishment of human induced pluripotent stem cells derived from skin cells of a patient with Dravet syndrome.2020

    • Author(s)
      Kimura Y, Tanaka Y, Shirasu N, Yasunaga S, Higurashi N, Hirose S.
    • Journal Title

      Stem Cell Res.

      Volume: 47 Pages: 101857-101857

    • DOI

      10.1016/j.scr.2020.101857

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Application of induced pluripotent stem cells in epilepsy2020

    • Author(s)
      Hirose Shinichi、Tanaka Yasuyoshi、Shibata Mami、Kimura Yuichi、Ishikawa Mitsuru、Higurashi Norimichi、Yamamoto Toshiyuki、Ichise Eisuke、Chiyonobu Tomohiro、Ishii Atsushi
    • Journal Title

      Molecular and Cellular Neuroscience

      Volume: 108 Pages: 103535-103535

    • DOI

      10.1016/j.mcn.2020.103535

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] KCNQ2遺伝子のミスセンス変異を共有するてんかん性脳症と良性てんかんの分子病態をmRNA-Seqにより解明する2020

    • Author(s)
      柴田磨己、石井敦士、廣瀨伸一
    • Journal Title

      てんかん治療研究振興財団 研究年報

      Volume: 31 Pages: 9-16

    • Related Report
      2020 Annual Research Report
  • [Journal Article] ドラベ(Dravet)症候群の病態分子基盤の解析および創薬を見据えた患者iPS細胞の作製2020

    • Author(s)
      木村雄一、廣瀨伸一
    • Journal Title

      Research

      Volume: 25 Pages: 5-37

    • Related Report
      2020 Annual Research Report
  • [Presentation] Research Experience sharing in Childhood Neurologic channelopathy disorders2023

    • Author(s)
      Hirose Shinichi
    • Organizer
      TCNS Mentoring lecture Conference
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Neurologic disorder in childhood channelopathy:from basicto clinic2022

    • Author(s)
      Hirose S
    • Organizer
      Ion channels: Structure, function, and disease- associated channelopathies
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Modulation of excitatory synaptic release in the single neuron by human-induced pluripotent stem cell-derived astrocytes2022

    • Author(s)
      Kouya Uchino, Yasuyoshi Tanaka, Sayaka Kawaguchi,  Kaori Kubota, Takuya Watanabe, Shutaro Katsurabayashi, Shinichi Hirose, Katsunori Iwasaki
    • Organizer
      NEURO2022 (ポスター)
    • Related Report
      2022 Annual Research Report
  • [Presentation] The establishment of a novel autaptic culture system equipped with human-induced pluripotent stem cell-derived astrocytes2022

    • Author(s)
      Kouya Uchino, Yasuyoshi Tanaka, Sayaka Kawaguchi, Kaori Kubota, Takuya Watanabe, Shutaro Katsurabayashi, Shinichi Hirose, Katsunori Iwasaki
    • Organizer
      Neuroscience meeting (ポスター)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 神経変性疾患の病態解明に資するiPSアストロサイトによる最小神経回路の構築2022

    • Author(s)
      Kouya Uchino, Yasuyoshi Tanaka, Sayaka Kawaguchi, Kaori Kubota, Takuya Watanabe, Shutaro Katsurabayashi, Shinichi Hirose & Katsunori Iwasaki
    • Organizer
      第96 回日本薬理学会年会 (ポスター)
    • Related Report
      2022 Annual Research Report
  • [Presentation] Application of induced pluripotent stem cells in epilepsy2021

    • Author(s)
      Hirose Shinichi
    • Organizer
      5th Azalea Festival symposium in Pediatric Neurology
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Drug discovery based on the etiologies of epilepsy using induced pluripotent stem cells2021

    • Author(s)
      Hirose Shinichi
    • Organizer
      5th Azalea Festival symposium in Pediatric Neurology
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 福岡大学医学部小児科でのてんかんの分子病態研究の歩み2021

    • Author(s)
      廣瀨 伸一
    • Organizer
      第512回日本小児科学会福岡地方会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 臨床科でもここまでできた!~福岡大学小児科でのてんかん分子病態研究~2021

    • Author(s)
      廣瀨伸一
    • Organizer
      第88回さが小児科地方会 第212回日本小児科学会長崎地方会合同地方会(ハイブリット開催)(2021.7.4.佐賀 web
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 福岡大学でのてんかんの分子病態研究-遺伝子から創薬への道2021

    • Author(s)
      廣瀨伸一
    • Organizer
      第44回 日本小児遺伝学会学術集会、第3回 日本ダウン症学会学術集会、第3回 日本ダウン症学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 分子病態に基づくてんかんの根治を目指して2021

    • Author(s)
      廣瀨伸一
    • Organizer
      愛知県医療療育総合センター 発達障害研究所 公開セミナー
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Development of novel drugs based on the pathomechanisms of developmental epileptic encephalopathy with disease specific induced pluripotent cells.2020

    • Author(s)
      Shnichi Hirose
    • Organizer
      2020Educational Seminar of Genetic & Metabolic Diseases for Young Pediatricians/ Investigators (SGMDYPI)
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Studies on the pathomechanisms of developmental and epileptic encephalopathy using induced pluripotent stem cells.2020

    • Author(s)
      Shnichi Hirose
    • Organizer
      21st Annual Meeting of the Infantile Seizure Society International Symposium on the Pathophysiology of Developmental and Epileptic Encephalopathy
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] てんかん専門医ガイドブック 2020;改訂第2版2020

    • Author(s)
      廣瀨伸一
    • Publisher
      診断と治療社
    • ISBN
      9784787824172
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] ナトリウムチャネル結合剤及び医薬組成物2020

    • Inventor(s)
      廣瀬伸一、田中泰圭、柴田磨己
    • Industrial Property Rights Holder
      廣瀬伸一、田中泰圭、柴田磨己
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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