Analysis of molecular pathology of Charcot-Marie-Tooth disease and search for therapeutic drugs

• Project/Area Number: 26461275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kagoshima University
• Principal Investigator: Okamoto Yuji 鹿児島大学, 医歯学域医学系, 講師 (60709658)
• Co-Investigator(Kenkyū-buntansha): 中川 正法 京都府立医科大学, 医学(系)研究科(研究院), 教授 (50198040) ; 高嶋 博 鹿児島大学, 医歯学域医学系, 教授 (80372803)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: Charcot-Marie-Tooth病 / 次世代シークエンサー / クルクミン / HMSN-P / 小胞体ストレス / ニューロパチー / 治療 / クルミン / アポトーシス

Outline of Final Research Achievements

We identified the effectiveness and mechanism of action of curcumin treatment in CMT model mice. It was also confirmed in model mice that curcumin reduces the endoplasmic reticulum stress response caused by abnormal protein accumulation with genetic mutation and alleviates apoptosis. In this study, we examined the administration of curcumin to humans. The primary problem in curcumin therapy is the low bioavailability, but we identified drugs with high bioavailability. We have prepared a system to conduct clinical trials for human during this research period. Most clinical trials other than CMT 1A are not done. We are also planning other types of CMT trials taking into account the efficacy of curcumin.
It is also important to identify the causative gene for treatment. We conducted comprehensive genetic diagnosis of CMT causative genes using next generation sequencers. As a result, 42 causative genes were identified in 23 (18%) of the 182 patients. I also found a new causative gene.

Research Products

• [Journal Article] WNK1/HSN2 Founder Mutation in Patients with Hereditary Sensory and Autonomic Neuropathy: a Japanese cohort study. (2017)
  • Author(s): Yuan JH, Hashiguchi A, Yoshimura A, Sakai N, Takahashi MP, Ueda T, Taniguchi A, Okamoto S, Kanazawa N7, Yamamoto Y, Saigoh K, Kusunoki S, Ando M, Hiramatsu Y, Okamoto Y, Takashima H.
  • Journal Title: Clin Genet. Volume: － Issue: 6 Pages: 659-663
  • DOI: 10.1111/cge.13037
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical diversity caused by novel IGHMBP2 variants. (2017)
  • Author(s): Yuan JH, Hashiguchi A, Yoshimura A, Yaguchi H, Tsuzaki K, Ikeda A, Wada-Isoe K, Ando M, Nakamura T, Higuchi Y, Hiramatsu Y, Okamoto Y, Takashima H.
  • Journal Title: J Hum Genet. Volume: － Issue: 6 Pages: 599-604
  • DOI: 10.1038/jhg.2017.15
  • NAID: 40021195533
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical and mutational spectrum of Japanese patients with Charcot-Marie-Tooth disease caused by GDAP1 variants. (2017)
  • Author(s): Yoshimura A, Yuan JH, Hashiguchi A, Hiramatsu Y, Ando M, Higuchi Y, Nakamura T, Okamoto Y, Matsumura K, Hamano T, Sawaura N, Shimatani Y, Kumada S, Okumura Y, Miyahara J, Yamaguchi Y, Kitamura S, Haginoya K, Mitsui J, Ishiura H, Tsuji S, Takashima H.
  • Journal Title: Clin Genet. Volume: － Issue: 3 Pages: 274-280
  • DOI: 10.1111/cge.13002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mutations in MME cause an autosomal-recessive Charcot-Marie-Tooth disease type 2. (2016)
  • Author(s): Higuchi Y, Hashiguchi A, Yuan J, Yoshimura A, Mitsui J, Ishiura H, Tanaka M, Ishihara S, Tanabe H, Nozuma S, Okamoto Y, Matsuura E, Ohkubo R, Tsuji S, Takashima .
  • Journal Title: Ann Neurol. Volume: Epub Issue: 4 Pages: 659-672
  • DOI: 10.1002/ana.24612
  • Peer Reviewed / Open Access
• [Journal Article] Charcot-Marie-Tooth病の遺伝子診断の進歩と治療法の開発 (2015)
  • Author(s): 岡本 裕嗣
  • Journal Title: Peripheral Nerve Volume: 26 (2) Pages: 226-231
• [Journal Article] Neurofilament light mutation causes hereditary motor and sensory neuropathy with pyramidal signs. (2014)
  • Author(s): Hashiguchi A, Higuchi Y, Nomura M, Nakamura T, Arata H, Yuan J, Yoshimura A, Okamoto Y, Matsuura E, Takashima H.
  • Journal Title: J Peripher Nerv Syst. Volume: 19 Issue: 4 Pages: 311-316
  • DOI: 10.1111/jns.12102
  • Peer Reviewed / Open Access
• [Journal Article] 遺伝性ニューロパチーの治療とその分子メカニズム (2014)
  • Author(s): 岡本裕嗣
  • Journal Title: Periferal Nerve Volume: 25 Pages: 207-213
• [Presentation] Next-generation sequencing analysis for mitochondrial disorders in adult Japanese patients. (2016)
  • Author(s): Y. Okamoto; J. Yuan; A. Yoshimra; Y. Hiramatsu; M. Ando; A. Hashiguchi; H. Takashima
  • Organizer: ASHG2016
  • Place of Presentation: Vancouver (Canada)
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Charcot-Marie-Tooth diseaseにおけるミトコンドリア関連遺伝子の検討 (2016)
  • Author(s): 平松 有, 岡本裕嗣,吉村明子, 安藤匡宏, 袁 軍輝，橋口昭大,樋口雄二郎, 辻 省次, 髙嶋 博
  • Organizer: 日本末梢神経学会学術集会
  • Place of Presentation: 大阪国際会議場 (大阪府,大阪市）
  • Year and Date: 2016-08-26
• [Presentation] 次世代シークエンサーを用いたミトコンドリア病の原因遺伝子の同定 (2016)
  • Author(s): 岡本裕嗣, 平松 有, 吉村明子, 袁 軍輝，安藤匡宏, 樋口雄二郎, 橋口昭大, 石浦浩之, 三井純, 辻 省次, 髙嶋 博
  • Organizer: 日本神経学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県,神戸市）
  • Year and Date: 2016-05-18
• [Presentation] シャルコー・マリー・トゥース病の診療のポイント (2016)
  • Author(s): 岡本裕嗣
  • Organizer: 日本神経学会学術集会
  • Place of Presentation: 神戸国際会議場（兵庫県,神戸市）
  • Year and Date: 2016-05-18
  • Invited
• [Presentation] Charcot-Marie-Tooth病の遺伝子診断の進歩と 治療法の開発 (2015)
  • Author(s): 岡本裕嗣
  • Organizer: 第26回日本末梢神経学会学術集会
  • Place of Presentation: ホテルブエナビスタ (長野県松本市）
  • Year and Date: 2015-09-18
• [Presentation] 遺伝性ニューロパチーの治療とその分子メカニズム (2014)
  • Author(s): 岡本裕嗣
  • Organizer: 第25回 日本末梢神経学会学術集会
  • Place of Presentation: 京都 ホテル ルビノ京都堀川
  • Year and Date: 2014-08-29