Research on PCDH19 female epilepsy by using patient-derived iPS cells and a rat model

• Project/Area Number: 24791095
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Jikei University School of Medicine (2013-2014); Fukuoka University (2012)
• Principal Investigator: HIGURASHI Norimichi 東京慈恵会医科大学, 医学部, 助教 (40568820)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: てんかん / 女性 / 遺伝子 / 疾患モデル動物 / 免疫 / 血液脳関門 / 接着分子 / 小児 / iPS細胞 / 脳血液関門

Outline of Final Research Achievements

To elucidate the pathogenic mechanisms and effective treatments of PCDH19 female epilepsy, we established 1) patient-derived iPS cells and 2) a model rat, and 3) further investigated the clinical aspects of newly identified patients. 1) We compared iPS cell-derived neurons among a normal control cell line, paternal X (mutated PCDH19)-active patient cell lines, and maternal X (wild type PCDH19)-active patient cell lines focusing on their morphology and PCDH19 expression. However, no significant pathogenic alteration was detected. 2) A Pcdh19-knockout rat was successfully established by using the TALEN technology and will be used for our future research. 3) We newly identified more than 20 Japanese patients and deepened our understanding of the clinical aspects of PCDH19 female epilepsy, specifically initial seizure characteristics, an excellent efficacy of corticosteroids for seizure clusters, and a possible involvement of immune processes in the pathogenic mechanisms.

Research Products

• [Journal Article] Immediate suppression of seizure clusters by corticosteroids in PCDH19 female epilepsy. (2015)
  • Author(s): Higurashi N, Takahashi Y, Kashimada A, Sugawara Y, Sakuma H, Tomonoh Y, Inoue T, Hoshina M, Satomi R, Ohfu M, Itomi K, Takano K, Kirino T, Hirose S.
  • Journal Title: Seizure Volume: 27 Pages: 1-5
  • DOI: 10.1016/j.seizure.2015.02.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy. (2015)
  • Author(s): Kano S, Yuan M, Cardarelli RA, Maegawa G, Higurashi N, et al.
  • Journal Title: Currrent Molecular Medicine Volume: 15 Issue: 2 Pages: 138-145
  • DOI: 10.2174/1566524015666150303110300
  • Peer Reviewed
• [Journal Article] 女性に発症するPCDH19関連てんかんの本邦例における臨床的特徴 (2013)
  • Author(s): 日暮憲道、他
  • Journal Title: てんかん治療研究財団研究年報 Volume: 24 Pages: 79-86
• [Journal Article] The effect of SCN1A mutations on patient-derived GABAergic neurons: what are the implications for future Dravet syndrome therapeutics? (2013)
  • Author(s): Higurashi N, Okano H, Hirose S.
  • Journal Title: Future Neurol Volume: 8 Issue: 5 Pages: 487-489
  • DOI: 10.2217/fnl.13.34
  • Peer Reviewed
• [Journal Article] Current Trends in Dravet syndrome Research. (2013)
  • Author(s): Higurashi N, Uchida T, Hirose S, Okano H.
  • Journal Title: J Neurol Neurophysiol. Volume: 4 Issue: 03 Pages: 152-152
  • DOI: 10.4172/2155-9562.1000152
  • Peer Reviewed
• [Journal Article] PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy. (2013)
  • Author(s): Higurashi N, Nakamura M, Sugai M, Ohfu M, Sakauchi M, Sugawara Y, Nakamura K, Kato M, Usui D, Mogami Y, Fujiwara Y, Ito T, Ikeda H, Imai K, Takahashi Y, Nukui M, Inoue T, Okazaki S, Kirino T, Tomonoh Y, Inoue T, Takano K, Shimakawa S, Hirose S.
  • Journal Title: Epilepsy Res Volume: 106 Issue: 1-2 Pages: 191-199
  • DOI: 10.1016/j.eplepsyres.2013.04.005
  • Peer Reviewed
• [Journal Article] A human Dravet syndrome model from patient induced pluripotent stem cells. (2013)
  • Author(s): Higurashi N, Uchida T, Lossin C, Misumi Y, Okada Y, Akamatsu W, Imaizumi Y, Zhang B, Nabeshima K, Mori MX, Katsurabayashi S, Shirasaka Y, Okano H, Hirose S.
  • Journal Title: Mol Brain Volume: 6 Issue: 1 Pages: 19-19
  • DOI: 10.1186/1756-6606-6-19
  • Peer Reviewed
• [Presentation] Inflammatory aspects of PCDH19-related epilepsy. (2014)
  • Author(s): Higurashi N, et al.
  • Organizer: 第48回日本てんかん学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-02
• [Presentation] A Powerful Treatment Option for PCDH19-related Epilepsy. (2014)
  • Author(s): Higurashi N, Hirose S
  • Organizer: PCDH19 Pediatric Epilepsy Professional and Family Symposium
  • Place of Presentation: サンフランシスコ（米国）
  • Year and Date: 2014-09-06
  • Invited
• [Presentation] Dravet syndrome research using patient-derived induced pluripotent stem cells—Present findings and future directions. (2014)
  • Author(s): Higurashi N, Hirose S
  • Organizer: Korea Epilepsy Congress (KEC 2014)
  • Place of Presentation: ソウル（韓国）
  • Year and Date: 2014-06-14
  • Invited
• [Presentation] シンポジウム：iPS細胞を用いた小児神経疾患の病態解明への期待とその問題点 ②てんかんの病態研究とその問題点 (2014)
  • Author(s): 日暮憲道
  • Organizer: 第56回日本小児神経学会総会
  • Place of Presentation: 浜松
  • Year and Date: 2014-05-29
  • Invited
• [Presentation] High prevalence of autoantibodies to N-methyl-D-aspartate receptor and the efficacy of glucocorticoids in PCDH19-related female-limited epilepsy. (2014)
  • Author(s): Higurashi N, et al.
  • Organizer: 13th International Child Neurology Congress
  • Place of Presentation: イグアス市（ブラジル）
  • Year and Date: 2014-05-05
• [Presentation] Potentials of induced pluripotent stem cell-derived neurons in future drug discovery for Dravet syndrome. (2014)
  • Author(s): Higurashi N, et al.
  • Organizer: The 7th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 大阪
• [Presentation] Modeling Dravet syndrome using induced pluripotent stem cells (2013)
  • Author(s): Higurashi N., et al.
  • Organizer: Pediatric Academic Societies Annual Meeting 2013
  • Place of Presentation: 米国 ワシントンDC
• [Presentation] A new research platform for Dravet syndrome using patient-derived induced pluripotent stem cells (2013)
  • Author(s): Higurashi N., et al.
  • Organizer: XII Workshop on Neurobiology of Epilepsy (WONOEP 2013)
  • Place of Presentation: カナダ ケベック州ローレンシャン
• [Presentation] PCDH19関連てんかんにおける発症初期の臨床的特徴と治療効果の検討 (2013)
  • Author(s): 日暮憲道、他
  • Organizer: 第55回日本小児神経学会学術総会
  • Place of Presentation: 大分市
• [Presentation] 患者由来iPS細胞によるDravet症候群モデルの確立と分化GABA性神経細胞における機能低下 (2013)
  • Author(s): 日暮憲道、他
  • Organizer: 第47回日本てんかん学会
  • Place of Presentation: 北九州市
• [Presentation] Dravet Syndrome or EFMR, What Is The Difference? – Can You Tell The Difference? (2012)
  • Author(s): Higurashi N., et al.
  • Organizer: International Child Neurology Congress & 11th Asian & Oceanian Congress of Child Neurology
  • Place of Presentation: オーストラリア ブリスベン
  • Invited
• [Presentation] Challenges in The Establishment of A Dravet Syndrome Model Using Patient-Derived iPS Cells. (2012)
  • Author(s): Higurashi N., et al.
  • Organizer: Korean Epilepsy Congress 2012
  • Place of Presentation: 大韓民国 仁川
  • Invited
• [Presentation] Research on clinical aspects of PCDH19-related epilepsy and induced pluripotent stem cells from a patient with Dravet syndrome: Present findings and future directions.
  • Author(s): Higurashi N, et al.
  • Organizer: 7th IGAKUKEN International Symposium on “Fever, Inflammation, and Epilepsy”
  • Place of Presentation: 東京
  • Invited
• [Presentation] Early clinical features and treatment efficacy of antiepileptic drugs in Japanese patients with PCDH19-related epilepsy.
  • Author(s): Higurashi N, et al.
  • Organizer: 2nd Edition of World Conference on PCDH19
  • Place of Presentation: ローマ（イタリア）
  • Invited
• [Presentation] Dravet症候群とPCDH19関連てんかん―診断・鑑別のポイントと発症病態．
  • Author(s): 日暮憲道
  • Organizer: 第47回日本てんかん学会
  • Place of Presentation: 北九州
  • Invited
• [Presentation] Modeling Dravet syndrome with patient-derived induced pluripotent stem cells and functional vulnerabilities in differentiated GABAergic neurons.
  • Author(s): Higurashi N, et al.
  • Organizer: 第47回日本てんかん学会
  • Place of Presentation: 北九州
• [Presentation] PCDH19関連てんかんにおける発症初期の臨床的特徴と治療効果の検討
  • Author(s): 日暮憲道、他
  • Organizer: 第55回日本小児神経学会総会
  • Place of Presentation: 大分
• [Presentation] A new research platform for Dravet syndrome using patient-derived induced pluripotent stem cells
  • Author(s): Higurashi N, et al.
  • Organizer: XII. Workshop on Neurobiology of the Epilepsy (WONOEP 2013)
  • Place of Presentation: ケベック（カナダ）
  • Invited
• [Presentation] Modeling Dravet Syndrome Using Induced Pluripotent Stem Cells.
  • Author(s): Higurashi N, et al.
  • Organizer: Pediatric Academic Societies Annual Meeting (PAS 2013)
  • Place of Presentation: ワシントンDC（米国）
  • Invited
• [Book] 遺伝子医学MOOK 27号 iPS細胞を用いた難病研究－臨床病態解明と創薬に向けた研究の最新知見 (2015)
  • Author(s): 4.日暮憲道, 廣瀬伸一
  • Total Pages: 228
  • Publisher: メディカル ドゥ
• [Book] 症例から学ぶ 戦略的てんかん診断・治療 (2014)
  • Author(s): 日暮憲道，井原由紀子，廣瀬伸一
  • Total Pages: 242
  • Publisher: 南山堂
• [Book] 日本臨牀別冊 神経症候群VI (2014)
  • Author(s): 日暮憲道, 廣瀬伸一
  • Total Pages: 1000
  • Publisher: 日本臨牀社
• [Book] 稀少難治てんかん診療マニュアル―疾患の特徴と診断のポイント (2013)
  • Author(s): 日暮憲道、他
  • Total Pages: 170
  • Publisher: 診断と治療社
• [Book] 子どものけいれん・てんかん 見つけ方・見分け方から治療戦略へ (2013)
  • Author(s): 日暮憲道、他
  • Total Pages: 268
  • Publisher: 中山書店