Drug discovery study improves the outcomes of epileptic encephalopathy

• Project/Area Number: 15K09628
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: CHIYONOBU Tomohiro 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40571659)
• Research Collaborator: YOSHIDA Michiko ; YAMASHITA Satoshi ; MAEDA Hiroshi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: てんかん性脳症 / iPS細胞 / 発達遅滞 / STXBP1 / syntaxin-1 / SCN1A / 精神運動発達遅滞

Outline of Final Research Achievements

We have partially elucidated the pathophysiology of two examples of epileptic encephalopathies, Ohtahara syndrome and Dravet syndrome, using patient-derived induced pluripotent stem (iPS) cells. Ohtahara syndrome, which is caused by mutation of the STXBP1 gene, was found to decrease levels of syntaxin-1, which in turn leads to localized abnormalities. In addition, Dravet syndrome, which is caused by mutation of the SCN1A gene, was found to increase levels of tyrosine hydroxylase, accelerating dopamine synthesis. Compounds that can improve the relevant cellular phenotypes in vitro could form the foundation of novel treatment to improve outcomes in epileptic encephalopathy.

Research Products

• [Journal Article] Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum (2017)
  • Author(s): Yoshida M.、Nakashima M.、Okanishi T.、Kanai S.、Fujimoto A.、Itomi K.、Morimoto M.、Saitsu H.、Kato M.、Matsumoto N.、Chiyonobu T.
  • Journal Title: Clinical Genetics Volume: 93 Issue: 2 Pages: 368-373
  • DOI: 10.1111/cge.13067
  • Peer Reviewed
• [Journal Article] Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome. (2016)
  • Author(s): Maeda H, Chiyonobu T, Yoshida M, Yamashita S, Zuiki M, Kidowaki S, Isoda K, Yamakawa K, Morimoto M, Nakahata T, Saito MK, Hosoi H.
  • Journal Title: J Hum Genet. Volume: 印刷中 Issue: 6 Pages: 565-569
  • DOI: 10.1038/jhg.2016.5
  • NAID: 40020857171
  • Peer Reviewed / Open Access
• [Journal Article] Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy. (2016)
  • Author(s): Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kidowaki S, Isoda K, Morimoto M, Kato M, Saitsu H, Matsumoto N, Nakahata T, Saito MK, Hosoi H
  • Journal Title: Epilepsia Volume: 57 Issue: 4
  • DOI: 10.1111/epi.13338
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] A human iPSC model of STXBP1-related epileptic encephalopathy uncovers specific neural dysfunctions. (2017)
  • Author(s): Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kidowaki S, Isoda K, Kato M, Saitsu H, Matsumoto N, Morimoto M
  • Organizer: 14th Asian and Oceanian Congress of Child Neurology
  • Int'l Joint Research
• [Presentation] SCN1A変異モザイク個人由来iPS細胞の樹立と病態解析への応用． (2016)
  • Author(s): 前田裕史, 千代延友裕，吉田路子, 山下哲史, 瑞木匡，木戸脇智志，磯田賢一，森本昌史．
  • Organizer: 第50回日本てんかん学会学術集会
  • Place of Presentation: 静岡
  • Year and Date: 2016-10-07
• [Presentation] Modeling the cellular phenotype of STXBP1-related epileptic encephalopathy using iPSC. (2016)
  • Author(s): Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kidowaki S, Isoda K, Morimoto M, Kato M, Saitsu H, Matsumoto N, Nakahata T, Saito MK, Hosoi H.
  • Organizer: 第58回日本小児神経学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-06-02
• [Presentation] Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome. (2016)
  • Author(s): Chiyonobu T, Maeda H, Yoshida M, Yamashita S, Zuiki M, Nakahata T, Saito MK, Morimoto M.
  • Organizer: The 14th International Child Neurology Congress.
  • Place of Presentation: Amsterdam, the Netherlands.
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] Modeling the cellular phenotype of STXBP1-related epileptic encephalopathy using iPSC. (2016)
  • Author(s): Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kato M, Saitsu H, Matsumoto N, Nakahata T, Saito MK, Morimoto M.
  • Organizer: The 14th International Child Neurology Congress.
  • Place of Presentation: Amsterdam, the Netherlands.
  • Year and Date: 2016-05-01
  • Int'l Joint Research
• [Presentation] Isogenic iPSCs from an individual with SCN1A mutation mosaicism revealed aberrant dopamine levels in Dravet syndrome neurons. (2015)
  • Author(s): Maeda H, Chiyonobu T, Yoshida M, Yamashita S, Zuiki M, Kidowaki S, Isoda K, Morimoto M, Nakahata T, Saito MK, Hosoi H
  • Organizer: Society for Neuroscience 45th Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Mislocalization of syntaxin-1 and impaired neurite growth observed in a human iPSC model for STXBP1-related epileptic encephalopathy. (2015)
  • Author(s): Yamashita S, Chiyonobu T, Yoshida M, Maeda H, Zuiki M, Kidowaki S, Isoda K, Morimoto M, Kato M, Saitsu H, Matsumoto N, Nakahata T, Saito MK, Hosoi H
  • Organizer: Society for Neuroscience 45th Annual Meeting
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Refractory epileptic encephalopathy in a case with cardio-facio-cutaneous syndrome caused by MAP2K1 mutation. (2015)
  • Author(s): Chiyonobu T, Kato M, Maeda H, Kidowaki S, Yamashita S, Zuiki M, Morimoto M, Nakashima M, Matsumoto N, Hosoi H
  • Organizer: The 13th Asian and Oceanian Congress of Child Neurology
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2015-05-14
  • Int'l Joint Research