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Copper supplement therapy based on a developmental change in copper metabolism in Menkes disease.

Research Project

Project/Area Number 16K09959
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Pediatrics
Research InstitutionTohoku University

Principal Investigator

Munakata Mitsutoshi  東北大学, 医学系研究科, 非常勤講師 (30312573)

Co-Investigator(Kenkyū-buntansha) 児玉 浩子  帝京大学, 医学部, 講師 (00093386)
高橋 秀依  東京理科大学, 薬学部薬学科, 教授 (10266348)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsMenkes病 / macular mouse / Cu-GTSM / Macular mouse / ATP7A / 銅 / 銅錯体 / Menkes病 / 治療法
Outline of Final Research Achievements

Menkes disease is a severe X-chromosome-linked disorder caused by mutations in a copper transporter, ATP7A. Parenteral administration of copper-histidine for treatment of the disease has been burden of prolonged injections. Oral copper supplementation via glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) (Cu-GTSM), a lipophilic copper rescued male hemizygous macular mice (MoMl/y), a mouse model of Menkes disease. However, in suckling macular mice, the Cu-GTSM treatment transiently induced diarrhea, accompanied by extreme copper accumulation and altered villus morphology in the ileum. Combined oral administration of disulfiram (DSF), a precursor of diethyldithiocarbamate, a copper chelator, enable reducing a dose of Cu-GTSM and ameliorated Cu-GTSM-induced diarrhea. The combined use of Cu-GTSM and DSF may decrease the chance of adverse enteral effects in oral administration of Cu-GTSM.

Academic Significance and Societal Importance of the Research Achievements

従来のMenkes病の治療法であるヒスチジン銅の皮下注射は中枢機能の回復が十分でなく、また長期にわたる皮下注射は患者側の負担が大きい。我々は脂溶性有機銅錯体による薬物治療のアプローチを行なっている。これらの化合物の特性を生かせば、経口・経胎盤など投与法の低侵襲かつ多彩な展開が期待できる。また、出生前診断法の発達も著しい。そこで、銅の体内動態の発達変化を踏まえ、胎児期を含めた治療を検討することは十分に意義がある。Menkes病は希少な疾患であり、大規模な治療薬開発のターゲットになりにくい。臨床の場からの創薬のチャレンジは社会的意義がある。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (5 results)

All 2018 2017 2016

All Journal Article (2 results) (of which Peer Reviewed: 1 results) Presentation (3 results)

  • [Journal Article] Menkes disease: Oral administration of glyoxal-bis(n(4)-methylthiosemicarbazonato)-copper(ii) rescues the macular mouse2018

    • Author(s)
      Munakata Mitsutoshi, Kodama Hiroko, Tani Norihiko, Kimura Kazuhiro, Takahashi Hideyo, Maruyama Kazuo, Sakamoto Yoshimasa, Kure Shigeo
    • Journal Title

      Pediatr Res.

      Volume: 84 Issue: 5 Pages: 770

    • DOI

      10.1038/s41390-018-0116-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In response to letter to Editor by Nosaka et al. on our paper: Elevated serum levels of neutrophil elastase in patients with influenza virus-associated encephalopathy.2017

    • Author(s)
      Haginoya K, Sun G, Ota C, Kitaoka S, Takayanagi M, Kitamura T, Uematsu M, Hino-Fukuyo N, Munakata M, Kure S.
    • Journal Title

      J Neurol Sci.

      Volume: 327 Pages: 50-50

    • DOI

      10.1016/j.jns.2016.11.041

    • Related Report
      2016 Research-status Report
  • [Presentation] Menkes病モデルマウス(Macular mouse)に対する有機銅錯体の経口投与の効果について2018

    • Author(s)
      宗形光敏、児玉浩子、谷紀彦、木村和彦、髙橋秀依、坂本吉正、呉繁夫
    • Organizer
      第22回日本ウイルソン病研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メンケス病モデル動物マクラマウスにおける CuGTSM の体内動態の検討2018

    • Author(s)
      小林昌平、川上武昭、阪本優介、宗形光敏、児玉浩子、高橋秀依、中村悠輔、山岸喜彰、工藤敏之、伊藤清美
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Menkes病モデルマウスに対する有機銅錯体経口投与による治療効果の検討2016

    • Author(s)
      宗形光敏、児玉浩子、谷紀彦、木村和彦、高橋英依、丸山一雄、呉繁夫
    • Organizer
      第58回日本先天代謝異常学会総会
    • Place of Presentation
      京王プラザホテル東京
    • Year and Date
      2016-10-27
    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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