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

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09959
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tohoku 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
• Keywords: Menkes病 / macular mouse / Cu-GTSM

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.

Free Research Field

小児科

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。