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2018 Fiscal Year Annual Research Report

To treat refractory epilepsy with transplantation of neuros derived from iPS cells.

Research Project

Project/Area Number 16K15532
Research InstitutionFukuoka University

Principal Investigator

廣瀬 伸一  福岡大学, 医学部, 教授 (60248515)

Project Period (FY) 2016-04-01 – 2019-03-31
Keywords小児神経 / てんかん / マウス / iPS細胞 / 実験動物
Outline of Annual Research Achievements

遺伝子変異を有する遺伝子改変動物にiPS細胞由来の神経細胞を移植し、難治性のてんかんの治療が可能か、検証するために、現在精神遅滞を伴う難治性てんかん(ドラベ症候群)のノックインマウスの二系統 (ナンセンス変異二種)をCRISPR/Cas9遺伝子編集法を使って作成した。ドラベ症候群は中枢神経電位依存性ナトリウムチャネルのα1サブユニットをコードする遺伝子SCN1Aの変異による、てんかん性脳症である。SCN1Aの変異は現在までに1200程度報告されており、60%がナンセンス変異を始めとするtruncating 変異と呼ばれ、α1サブユニットの分子途絶を引き起こす。その他の多くはミスセンス変異であり、アミノ酸置換を引き起こす。最近の我々の研究により、ナンセンス変異によるドラベ症候群はミスセンス変異によるものに比べ、精神遅滞が早期に重度に起こることが明らかにされた。このため、今回のドラベ症候群のモデルマウスの作出にナンセンス変異二種類を選んだ。我々がすでに作出した、SCN1Aを含む染色体微小欠失を持
つマウスでは、ヒトと同様のけいれんを来たし、早期突然死も観察されている。さらに、scn1a変異を数種持つマウスを作出した。
一方、アイソジェニックな人工“健常”iPS細胞および、人工“ドラベ症候群”細胞を作出することを見据え、ヒトドラベ症候群およびiPS細胞にTALEN遺伝子編
集法を使い、対照健常者由来のiPS細胞にSCN1Aの変異を導入、またドラベ症候群由来の患者iPS細胞のSCN1Aの変異の修復が終了し、論文として発表している。

  • Research Products

    (16 results)

All 2019 2018

All Journal Article (9 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 9 results) Presentation (7 results) (of which Int'l Joint Research: 7 results,  Invited: 1 results)

  • [Journal Article] Different types of suppression-burst patterns in patients with epilepsy of infancy with migrating focal seizures (EIMFS).2019

    • Author(s)
      Yoshitomi S, Takahashi Y, Imai K, Koshimizu E, Miyatake S, Nakashima M, Saitsu H, Matsumoto N, Kato M, Fujita T, Ishii A, Hirose S, Inoue Y.
    • Journal Title

      Seizure.

      Volume: 65 Pages: 118-23

    • DOI

      10.1016/j.seizure.2019.01.009

    • Peer Reviewed
  • [Journal Article] Generation of D1-1 TALEN isogenic control cell line from Dravet syndrome patient iPSCs using TALEN-mediated editing of the SCN1A gene.2018

    • Author(s)
      Tanaka Y, Sone T, Higurashi N, Sakuma T, Suzuki S, Ishikawa M, Yamamoto T, Mitsui J, Tsuji H, Okano H, Hirose S.
    • Journal Title

      Stem Cell Res.

      Volume: 28 Pages: 100-4

    • DOI

      10.1016/j.scr.2018.01.036

    • Peer Reviewed
  • [Journal Article] Establishment of a human induced stem cell line (FUi002-A) from Dravet syndrome patient carrying heterozygous R1525X mutation in SCN1A gene.2018

    • Author(s)
      Tanaka Y, Higurashi N, Shirasu N, Yasunaga S, Moreira KM, Okano H, Hirose S.
    • Journal Title

      Stem Cell Res.

      Volume: 31 Pages: 11-5

    • DOI

      10.1016/j.scr.2018.06.008

    • Peer Reviewed
  • [Journal Article] A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features.2018

    • Author(s)
      Okumura A, Maruyama K, Shibata M, Kurahashi H, Ishii A, Numoto S, Hirose S, Kawai T, Iso M, Kataoka S, Okuno Y, Muramatsu H, Kojima S.
    • Journal Title

      Brain Dev.

      Volume: 40(10) Pages: 926-30

    • DOI

      10.1016/j.braindev.2018.06.005

    • Peer Reviewed
  • [Journal Article] Somatic mosaic deletions involving SCN1A cause Dravet syndrome.2018

    • Author(s)
      Nakayama T, Ishii A, Yoshida T, Nasu H, Shimojima K, Yamamoto T, Kure S, Hirose S.
    • Journal Title

      Am J Med Genet A.

      Volume: 176(3) Pages: 657-62

    • DOI

      10.1002/ajmg.a.38596

    • Peer Reviewed
  • [Journal Article] Long-term follow up of an adult with alternating hemiplegia of childhood and a p.Gly755Ser mutation in the ATP1A3 gene.2018

    • Author(s)
      Ito T, Narugami M, Egawa K, Yamamoto H, Asahina N, Kohsaka S, Ishii A, Hirose S, Shiraishi H.
    • Journal Title

      Brain Dev.

      Volume: 40(3) Pages: 226-8

    • DOI

      10.1016/j.braindev.2017.11.007

    • Peer Reviewed
  • [Journal Article] CACNA1A-related early-onset encephalopathy with myoclonic epilepsy: A case report.2018

    • Author(s)
      Hayashida T, Saito Y, Ishii A, Yamada H, Itakura A, Minato T, Fukuyama T, Maegaki Y, Hirose S.
    • Journal Title

      Brain Dev.

      Volume: 40(2) Pages: 130-3

    • DOI

      10.1016/j.braindev.2017.08.006

    • Peer Reviewed
  • [Journal Article] Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report.2018

    • Author(s)
      Hayashida T, Saito Y, Ishii A, Hirose S, Hiraiwa R, Maegaki Y, Ohno K.
    • Journal Title

      Brain Dev.

      Volume: 40(7) Pages: 576-81

    • DOI

      10.1016/j.braindev.2018.03.004

    • Peer Reviewed
  • [Journal Article] Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy.2018

    • Author(s)
      Bailey JN, de Nijs L, Bai D, Suzuki T, Miyamoto H, Tanaka M, Patterson C, Lin YC, Medina MT, Alonso ME, Serratosa JM, Duron RM, Nguyen VH, Wight JE, Martinez-Juarez IE, Ochoa A, Jara-Prado A, Guilhoto L, Molina Y, Yacubian EM, Lopez-Ruiz M, Inoue Y, Kaneko S, Hirose S, et al.
    • Journal Title

      N Engl J Med.

      Volume: 378(11) Pages: 1018-28.

    • DOI

      10.1056/NEJMoa1700175

    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Genetic background of developmental and epileptic encephalopathies2018

    • Author(s)
      Hirose S,
    • Organizer
      KEC2018 23rd
    • Int'l Joint Research
  • [Presentation] Challenges and Opportunities in Pediatric Neurological Disease in Low Income Countries like Nepal2018

    • Author(s)
      Hirose S,
    • Organizer
      XIXth Nepalese Congress of Paediatrics,NEPCON 2018 & 37th Anniversary NEPAS
    • Int'l Joint Research / Invited
  • [Presentation] Precision medicine through stem cells2018

    • Author(s)
      Hirose S,
    • Organizer
      12th Asian and Oceanian Epilepsy Congress
    • Int'l Joint Research
  • [Presentation] Disease Modeling of Refractory Epilepsy using iPSCs2018

    • Author(s)
      Hirose S,
    • Organizer
      The 40th Annual Meeting of Japanese Society of Biological Psychiatry The 61st Annual Meeting of the Japanese Society for Neurochmistry
    • Int'l Joint Research
  • [Presentation] Genes in Focal Epilepsy2018

    • Author(s)
      Hirose S,
    • Organizer
      ANZCNS 7th Annual Scientific Meeting
    • Int'l Joint Research
  • [Presentation] Application of Genetics to Epilepsy after Gene-Hunting2018

    • Author(s)
      Hirose S,
    • Organizer
      Anzcns 7th Annual Scientific Meeting
    • Int'l Joint Research
  • [Presentation] Pathogenesis and genetic substrate2018

    • Author(s)
      Hirose S,
    • Organizer
      19th International symposium on severe infantile epilepsies: old and new treatments.
    • Int'l Joint Research

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Published: 2019-12-27  

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