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Treatment of congenital hypomyelinating leukodystrophy using the gene suppression effect of morpholino

Research Project

Project/Area Number 25670485
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Pediatrics
Research InstitutionNational Center of Neurology and Psychiatry

Principal Investigator

Inoue Ken  国立研究開発法人国立精神・神経医療研究センター, 神経研究所疾病研究第二部, 室長 (30392418)

Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywordsトランスレーショナルリサーチ / 脳神経疾患 / アンチセンス / 発現抑制 / 治療法開発 / トランスレーショナルリサーチレーショナルリサーチ / 発現制御
Outline of Final Research Achievements

Pelizaeus-Merzbacher disease is a hypomyelinating leukodystrophy characterized by failure of myelination. the most frequent mutation is PLP1 duplication that lead to gene overexpression, but no cure is available. In this study, we employed a synthetic antisense oligonucleotide-like reagent, morpholino, to develop a therapy for PLP1 duplication. We designed and produced modified morpholino that can specifically suppress PLP1 expression. We treated PLP1 trasngenic mice by injecting morpholino into ventricle or cerebral parenchyma. However, we found that morpholino is toxic to brain tissue and concluded that morpholino is inappropriate to use in the treatment of PLP1 duplication.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Research-status Report
  • 2013 Research-status Report
  • Research Products

    (27 results)

All 2016 2015 2014 2013 Other

All Journal Article (13 results) (of which Peer Reviewed: 13 results,  Acknowledgement Compliant: 2 results,  Open Access: 2 results) Presentation (14 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] The magnetic resonance imaging spectrum of Pelizaeus-Merzbacher disease: A multicenter study of 19 patients.2016

    • Author(s)
      Sumida K, Inoue K, Takanashi JI, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Mastuda H, Sato N
    • Journal Title

      Brain Dev

      Volume: in press Issue: 6 Pages: 571-80

    • DOI

      10.1016/j.braindev.2015.12.007

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A splicing mutation of proteolipid protein 1 in Pelizaeus-Merzbacher disease.2016

    • Author(s)
      Omata T, Nagai J, Shimbo H, Koizume S, Miyagi Y, Kurosawa K, Yamashita S, Osaka H, Inoue K.
    • Journal Title

      Brain & Development

      Volume: 38 Issue: 6 Pages: 581-584

    • DOI

      10.1016/j.braindev.2015.12.002

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Additive dominant effect of a SOX10 mutation underlies a complex phenotype of PCWH2015

    • Author(s)
      Ito Y, Inoue N, Inoue YU, Nakamura S, Matsuda Y, Inagaki M, Okubo T, Asami J, Terakawa YW, Kohsaka S, Goto Y, Akazawa C, Inoue T, Inoue K
    • Journal Title

      Neurobiology of Disease

      Volume: In Press Pages: 1-14

    • DOI

      10.1016/j.nbd.2015.04.013

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathophysiology and emerging therapeutic strategies in Pelizaeus-Merzbacher Disease.2015

    • Author(s)
      Osaka H, Inoue K.
    • Journal Title

      Expert Opinion on Orphan Drugs.

      Volume: 3 Issue: 12 Pages: 1447-1458

    • DOI

      10.1517/21678707.2015.1106315

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine.2014

    • Author(s)
      Morimura T, Numata Y, Nakamura S, Hirano E, Gotoh L, Goto YI, Urushitani M, Inoue K.
    • Journal Title

      Exp Biol Med

      Volume: 239 Issue: 4 Pages: 489-501

    • DOI

      10.1177/1535370213520108

    • Related Report
      2014 Research-status Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epidemiological, clinical, and genetic landscapes of hypomyelinating leukodystrophies.2014

    • Author(s)
      Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, Yamamoto T, Osaka H, Inoue K.
    • Journal Title

      J Neurol.

      Volume: 261(4) Issue: 4 Pages: 752-758

    • DOI

      10.1007/s00415-014-7263-5

    • Related Report
      2014 Research-status Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Involvement of ER Stress in Dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 Missense Mutations Shown by iPSC-Derived Oligodendrocytes2014

    • Author(s)
      Numasawa-Kuroiwa Y, Okada Y, Shibata S, Kishi N, Akamatsu W, Shoji M, Nakanishi A, Oyama M, Oasaka H, Inoue K, Takahashi K, Yamanaka S, Kosaki K, Takahashi T, Okano H
    • Journal Title

      Stem Cell Rep

      Volume: 2 Issue: 5 Pages: 1-14

    • DOI

      10.1016/j.stemcr.2014.03.007

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] SLC16A2 mutations in two Japanese patients with Allan–Herndon–Dudley syndrome.2014

    • Author(s)
      Yamamoto T, Shimojima K, Umemura A, Uematsu M, Nakayama T, Inoue K.
    • Journal Title

      HumGenVar

      Volume: 1 Issue: 1 Pages: 14010-14010

    • DOI

      10.1038/hgv.2014.10

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Three new PLP1 splicing mutations demonstrate pathogenic and phenotypic diversity of Pelizaeus-Merzbacher disease.2014

    • Author(s)
      Lassuthova P, Zaliova M, Inoue K, Haberlova J, Sixtova K, Sakmaryova I,Paderova K, Mazanec R, Zamecnik J, Siskova D, Garbern J, Seeman P.
    • Journal Title

      J Child Neurol

      Volume: 0 Issue: 7 Pages: 0-0

    • DOI

      10.1177/0883073813492387

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.2014

    • Author(s)
      Gotoh L, Inoue K, Helman G, Mora S, Maski K, Soul JS, Bloom M, Evans SH, Goto Y, Caldovic L, Hobson GM, Vanderver A.
    • Journal Title

      Mol Genet Metab.

      Volume: 111 Issue: 3 Pages: 393-8

    • DOI

      10.1016/j.ymgme.2013.12.001

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Partial PLP1 deletion causing X-linked dominant spastic paraplegia type 2.2013

    • Author(s)
      Matsufuji M, Osaka H, Gotoh L, Shimbo H, Takashima S, Inoue K
    • Journal Title

      Pediatric Neurology

      Volume: 49 Issue: 6 Pages: 477-81

    • DOI

      10.1016/j.pediatrneurol.2013.07.012

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations.2013

    • Author(s)
      98. Takanashi JI, Osaka H, Saitsu H, Sasaki M, Mori H, Shibayama H, Tanaka M,
    • Journal Title

      Brain Dev.

      Volume: May 3 Issue: 3 Pages: 259-263

    • DOI

      10.1016/j.braindev.2013.03.006

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] 先天性大脳白質形成不全症:ゲノム解析から診断、治療への取り組み2013

    • Author(s)
      井上 健,岩城明子,黒澤健司,高梨潤一,出口貴美子,山本俊至,小坂 仁
    • Journal Title

      脳と発達

      Volume: 45 Pages: 122-126

    • NAID

      10031156273

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Presentation] Seeking drugs for Pelizaeus-Merzbacher disease using drug repositioning approach targeting a novel cellular pathology.2015

    • Author(s)
      K Inoue, P.R. Mangalika, A Nishizawa, H Li, Y Numata, S Nakamura, T Morimura, H Saya, Y Goto.
    • Organizer
      The 65th American Society of Human Genetics Annual Meeting
    • Place of Presentation
      Baltimore Convention Center, Baltimore, USA
    • Year and Date
      2015-10-06
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 既存薬ドラッグ・リポジショニングによるPelizaeus-Merzbacher病の治療候補薬の探索2015

    • Author(s)
      井上 健、マンガリイ・プリアンティ、西澤絢子、李珩、沼田有里佳、中村祥子、守村敏史、佐谷秀行、後藤雄一
    • Organizer
      第57回日本小児神経学会総会
    • Place of Presentation
      大阪(帝国ホテル大阪)
    • Year and Date
      2015-05-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] PLP1点変異の新規分子病態を標的としたドラッグ・リポジショニングによるPelizaeus-Merzbacher病の治療法開発2014

    • Author(s)
      井上 健、マンガリイ・プリアンティ、沼田有里佳、中村祥子、守村敏史、佐谷秀行、後藤雄一
    • Organizer
      第59回日本人類遺伝学会
    • Place of Presentation
      東京(タワーホール船堀)
    • Year and Date
      2014-11-19 – 2014-11-22
    • Related Report
      2014 Research-status Report
  • [Presentation] dditive toxicity of SOX10 mutation underlies a complex neurological phenotype of PCWH2014

    • Author(s)
      Inoue K, Ito Y, Inoue N, Inoue YU, Nakamura S, Matsuda Y, Inagaki M, Ohkubo T, Asami J, Terakawa YW, Kohsaka S, Goto Y, Akazawa C, Inoue T.
    • Organizer
      The 64th American Society of Human Genetics Annual Meeting
    • Place of Presentation
      San Diego Convention Center, San Diego, USA
    • Year and Date
      2014-10-18 – 2014-10-22
    • Related Report
      2014 Research-status Report
  • [Presentation] bronx waltzerマウス変異遺伝子Srrm4の脳内発現とGABAergic interneuronへの影響2014

    • Author(s)
      白川 由佳、泉 仁美、中村 祥子、井上 健、後藤 雄一、稲垣 真澄
    • Organizer
      第37回神経科学会大会
    • Place of Presentation
      横浜(パシフィコ横浜)
    • Year and Date
      2014-09-11 – 2014-09-13
    • Related Report
      2014 Research-status Report
  • [Presentation] PLP1 missense mutations impair subcellular organelle dynamics that impact clinical severity of Pelizaeus-Merzbacher disease.2014

    • Author(s)
      Inoue K, Numata Y, Morimura T, Nakamura S, Goto Y
    • Organizer
      20th Biennial Meeting of the International Society for Developmental Neuroscience
    • Place of Presentation
      Hilton Montreal Bonaventure, Montreal, Canada
    • Year and Date
      2014-07-19 – 2014-07-24
    • Related Report
      2014 Research-status Report
  • [Presentation] Abnormal neuronal migration with ischemic brain injury in extremely preterm infants underlies subsequent cognitive impairment.2014

    • Author(s)
      K. Deguchi , K Kubo, K Nakajima K. Inoue.
    • Organizer
      20th Biennial Meeting of the International Society for Developmental Neuroscience
    • Place of Presentation
      Hilton Montreal Bonaventure, Montreal, Canada
    • Year and Date
      2014-07-19 – 2014-07-24
    • Related Report
      2014 Research-status Report
  • [Presentation] Pelizaeus-Merzbacher-like病:GJC2遺伝子の新規プロモーター変異とその分子病態2014

    • Author(s)
      井上 健、後藤玲央、Helman G, Mora S, Maski K, Soul JS, Bloom M, Evans SH, 後藤雄一, Caldovic L, Hobson GM, Vanderver A.
    • Organizer
      第56回日本小児神経学会総会
    • Place of Presentation
      浜松(アクトシティ浜松)
    • Year and Date
      2014-05-29 – 2014-05-31
    • Related Report
      2014 Research-status Report
  • [Presentation] Preclinical studies for the treatment of Pelizaeus-Merzbacher disease with clinically applicable compounds, curumin and chloroquine.2013

    • Author(s)
      Inoue K, Morimura T, Numata Y, Yu L-H, Gotoh L, Yamamoto R, Inoue N, Antalfy B, Deguchi K, Osaka H, Goto Y.
    • Organizer
      23rd Meeting of the European Neurological Society
    • Place of Presentation
      Barcelona, Spain(Fira de Barcelona)
    • Related Report
      2013 Research-status Report
  • [Presentation] Abnormal neuronal migration with ischaemic brain injuries may cause cognitive dysfunction in extremely preterm infants.2013

    • Author(s)
      Deguchi K, Kubo K, Armstrong D, Nakajima K, Inoue K.
    • Organizer
      23rd Meeting of the European Neurological Society
    • Place of Presentation
      Barcelona, Spain(Fira de Barcelona)
    • Related Report
      2013 Research-status Report
  • [Presentation] Brain N-acetylaspartate is Increased in mouse models of Pelizaeus-Merzbacher disease: implication for human imaging findings.2013

    • Author(s)
      Inoue K, Itoh Y, Saito S, Aoki I, Barkovich J, Takanashi J.
    • Organizer
      62rd Annual meeting of the American Society of Human Genetics
    • Place of Presentation
      Boston, USA(Boston Convention & Exhibition Center)
    • Related Report
      2013 Research-status Report
  • [Presentation] More than ER stress: molecular mechanism for misfolded PLP1 that impacts subcellular dynamics and clinical severity of Pelizaeus-Merzbacher disease.2013

    • Author(s)
      Numata Y, Morimura T, Nakamura S, Hirano E, Kure S, Goto Y, Inoue K.
    • Organizer
      62rd Annual meeting of the American Society of Human Genetics
    • Place of Presentation
      Boston, USA(Boston Convention & Exhibition Center)
    • Related Report
      2013 Research-status Report
  • [Presentation] 先天性大脳白質形成不全症の脳MRI画像データベース構築への取り組み

    • Author(s)
      井上 健、高梨潤一、小坂 仁、佐藤典子
    • Organizer
      第55回日本小児神経学会総会
    • Place of Presentation
      大分(大分オアシスタワーホテル)
    • Related Report
      2013 Research-status Report
  • [Presentation] Pelizaeus-Merzbacher病の細胞内分子病態:小胞体ストレスとシャペロンダイナミクス

    • Author(s)
      沼田有里佳、呉繁夫、後藤雄一、井上健
    • Organizer
      第55回日本小児神経学会総会
    • Place of Presentation
      大分(大分オアシスタワーホテル)
    • Related Report
      2013 Research-status Report

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Published: 2014-07-25   Modified: 2019-07-29  

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