Gene therapy for epilepsy by intravascular administration of Adeno-associated virus

• Project/Area Number: 25460501
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Jichi Medical University
• Principal Investigator: OGURO KEIJI 自治医科大学, 医学部, 准教授 (90231232)
• Co-Investigator(Kenkyū-buntansha): SHIMAZAKI Kuniko 自治医科大学, 脳神経外科, 非常勤講師 (40142153) ; YOKOTA Hidenori 自治医科大学, 脳神経外科, 講師 (90254929)
• Co-Investigator(Renkei-kenkyūsha): MURAMATSU Shinichi 自治医科大学, 神経内科, 教授 (10239543)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: てんかん / 遺伝子治療 / ELマウス / てんかん遺伝子治療 / AAVベクター / ミニブタ

Outline of Final Research Achievements

The purpose of this project is to develop a new therapy for the intractable epilepsy patients resistant to the conventional therapies including medication and surgery. We developed a new gene therapy using Adeno Associated Virus (AAV) vector pass through the blood brain barrier (BBB) which enables us to intravascular administration. We performed intracardiac injection of AAV-Neuroligin2 on epileptic EL mice. Neuroligin2 is a synapse related molecule which is known to induce or accelerate the formation of GABAergic synapses. We found that administrated AAV-Neuroligin2 is expressed over the brain including cortex and hippocampus and successfully suppress the seizure.

Research Products

• [Journal Article] Determination of epileptic focus side in mesial temporal lobe epilepsy using long-term noninvasive fNIRS/EEG monitoring for presurgical evaluation. (2015)
  • Author(s): Rizki,EE, Uga M, Dan I, Dan H, Tsuzuki D, Yokota H, Oguro K, Watanabe E
  • Journal Title: Neurophotonics Volume: 2 Issue: 2 Pages: 0250031-13
  • DOI: 10.1117/1.nph.2.2.025003
  • Peer Reviewed / Open Access
• [Journal Article] Determination of epileptic focus side in mesial temporal lobe epilepsy using long-term non-invasive fNIRS/EEG monitoring for presurgical evaluation (2015)
  • Author(s): Rizki E, Uga M, Dan I, Dan H, Tsuzuki D, Mizutani T, Sano T, Yokota H, Oguro K, and Watanabe E
  • Journal Title: Neurophotonics Volume: 2
• [Journal Article] Anterograde C1ql1 signaling is required in order to determine and maintain a single-winner climbing fiber in the mouse cerebellum. (2015)
  • Author(s): Kakegawa W, Mitakidis N, Miura E, Abe M, Matsuda K, Takeo YH, Kohda K, Motohashi J, Takahashi A, Nagao S, Muramatsu SI, Watanabe M, Sakimura K, Aricescu AR, Yuzaki M
  • Journal Title: Neuron Volume: 85 Issue: 2 Pages: 316-329
  • DOI: 10.1016/j.neuron.2014.12.020
  • Peer Reviewed / Open Access
• [Journal Article] In utero gene therapy rescues microcephaly caused by Pqbp1-hypofunction in neural stem progenitor cells. (2015)
  • Author(s): Ito H, Shiwaku H, Yoshida C, Homma H, Luo H, Chen X, Fujita K, Musante L, Fischer U, Frints SG, Romano C, Ikeuchi Y, Shimamura T, Imoto S, Miyano S, Muramatsu SI, Kawauchi T, Hoshino M, Sudol M, Arumughan A, Wanker EE, Rich T, Schwartz C, Matsuzaki F, Bonni A, Kalscheuer VM, Okazawa H.
  • Journal Title: Mol Psychiatry Volume: 20 Issue: 4 Pages: 459-71
  • DOI: 10.1038/mp.2014.69
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Direct cortical hemodynamic mapping of somatotopy of pig nostril sensation by functional near-infrared cortical imaging (fNCI) (2014)
  • Author(s): Uga M, Saito T, Sano T, Yokota H, Oguro K, Rizki EE, Mizutani T, Katura T, Dan I, Watanabe E
  • Journal Title: NeuroImage Volume: 91 Pages: 138-145
  • DOI: 10.1016/j.neuroimage.2013.12.062
  • Peer Reviewed / Open Access
• [Journal Article] Electroconvulsive seizures enhance autophagy signaling in rat hippocampus (2014)
  • Author(s): Otabe H, Nibuya M, Shimazaki K, Toda H, Suzuki G, Nomura S, Shimizu K
  • Journal Title: Prog Neuropsychopharmacol Biol Psychiatry Volume: 50 Pages: 37-43
  • DOI: 10.1016/j.pnpbp.2013.11.012
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of Shati/Nat8l, an N-acetyltransferase, in the nucleus accumbens attenuates the response to methamphetamine via activation of group II mGluRs in mice. (2014)
  • Author(s): Miyamoto Y, Ishikawa Y, Iegaki N, Sumi K, Fu K, Sato K, Furukawa-Hibi Y, Muramatsu SI, Nabeshima T, Uno K, Nitta A.
  • Journal Title: Int J Neuropsychopharmacol Volume: 24 Pages: 1-12
• [Journal Article] Language-specific cortical activation patterns for verbal fluency tasks in Japanese as assessed by multichannel functional near-infrared spectroscopy (2013)
  • Author(s): Dan H, Dan I, Sano T, Kyutoku Y, Oguro K, Yokota H, Tsuzuki D, Watanabe E
  • Journal Title: Brain and Language Volume: 126 Issue: 2 Pages: 208-216
  • DOI: 10.1016/j.bandl.2013.05.007
  • Peer Reviewed
• [Journal Article] Clinical benefit of botulinum toxin therapy after selective peripheral denervation in torticollis. (2013)
  • Author(s): Tetsuka M, Nakajima T, Kimura Y, Yokota H, Oguro K, Taira T, Watanabe E.
  • Journal Title: Functional Neurosurgery Volume: 52 Pages: 166-169
  • NAID: 40021317575
• [Journal Article] Systemic delivery of tyrosine-mutant AAV vectors results in robust transduction of neurons in adult mice. (2013)
  • Author(s): Iida A, Takino N, Miyauchi H, Shimazaki K, Muramatsu S
  • Journal Title: Bio Med Res Int Volume: 2013 Pages: 974819-974819
  • DOI: 10.1155/2013/974819
  • Peer Reviewed
• [Presentation] ELマウスにおける血管内投与型アデノ随伴ウイルス(AAV)ベクターによるてんかんの遺伝子治療 (2015)
  • Author(s): 小黒恵司、島崎久仁子、横田英典、アリフ・ダハ、村島善也、 村松慎一、渡辺英寿
  • Organizer: 第49回日本てんかん学会
  • Place of Presentation: 長崎ブリックホール（長崎）
  • Year and Date: 2015-10-30
• [Presentation] Focus diagnosis for intractable epilepsy by fNIRS (2014)
  • Author(s): Oguro K, Yokota H, Mizutani T, Rizki EE Hirai M, Dan I, Watanabe E
  • Organizer: fNIRS 2014
  • Place of Presentation: Montreal, Canada
  • Year and Date: 2014-10-10 – 2014-10-12
• [Presentation] ELマウスにおけるてんかん発作時および間欠期脳血流の検討 (2014)
  • Author(s): 小黒恵司、島崎久仁子、横田英典、村島善也、間賀田泰寛、渡辺英寿
  • Organizer: 第48回日本てんかん学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-02 – 2014-10-03
• [Presentation] Diagnosis of focus side in intractable mesial temporal epilepsy by fNIRS during spontaneous seizure (2014)
  • Author(s): Oguro K, Yokota H, Mizutani T, Rizki EE Hirai M, Dan I, Watanabe E
  • Organizer: 11th European Congress on Epilepsy
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-29 – 2014-07-03
• [Presentation] 光トポグラフィーのてんかん焦点診断への応用 (2013)
  • Author(s): 小黒恵司, 横田英典, 水谷勉, 佐野史俊, リゼキ・エドミ・エジソン, 檀一平太, 渡辺英寿
  • Organizer: 第15回ヒト脳機能マッピング学会
  • Place of Presentation: 東京大学伊藤国際学術研究センター
  • Invited
• [Presentation] 栃木県におけるてんかん診療の実際とネットワーク構築 －エピネット栃木、紹介患者動向、1,2次診療施設アンケート調査－ (2013)
  • Author(s): 小黒恵司、横田英典、水谷 勉、渡辺英寿
  • Organizer: 第47回日本てんかん学会学術集会
  • Place of Presentation: 北九州国際会議場
• [Presentation] 栃木県におけるてんかん診療の実際と地域ネットワーク構築 －エピネット栃木、外来紹介患者動向、1,2次診療施設アンケート調査－ (2013)
  • Author(s): 小黒恵司、横田英典、渡辺英寿
  • Organizer: 第72回日本脳神経外科学会総会
  • Place of Presentation: パシフィコ横浜