Development of targeting therapy for sporadic ALS using RNA aptamers

• Project/Area Number: 26640036
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: The University of Tokyo
• Principal Investigator: Kwak Shin 東京大学, 医学(系)研究科(研究院), 研究員 (40160981)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脳神経疾患 / 神経科学 / 核酸

Outline of Final Research Achievements

Expression of abnormally calcium-permeable AMPA receptors that have Q/R site-unedited GluA2 subunit in their subunit assembly in the motor neurons is involved in the pathogenesis of sporadic ALS. We explored the possibility of stable RNA aptamers that effectively blocked Ca2+-permeable AMPA receptors as a drug for ALS using a mechanistic ALS mouse model. Using a subcutaneously placed mini-pump, the RNA aptamer was continuously infused intracerebroventricularly through an indwelling cannula. The RNA aptamer was safely delivered to brains and spinal cords without extensive degradation and effectively blocked abnormal Ca2+ influx into the cortical and spinal cord neurons. AMPA receptor-specific RNA aptamers may be a potential drug for ALS.

Research Products

• [Journal Article] Phosphorylated TDP-43 becomes resistant to cleavage by calpain: a regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD. (2016)
  • Author(s): Yamashita T, Teramoto S, Kwak S
  • Journal Title: Neurosci Res Volume: -
  • Peer Reviewed
• [Journal Article] Deficient RNA-editing enzyme ADAR2 in an amyotrophic lateral sclerosis patient with a FUSP525L mutation. (2016)
  • Author(s): Aizawa H, Hideyama T, Yamashita T, Kimura T, Suzuki N, Aoki M, Kwak S
  • Journal Title: J Clin Neurosci Volume: -
  • Peer Reviewed
• [Journal Article] Anti-TIF1-g antibody and cancer-associated myositis:a clinicohistopathological study. (2016)
  • Author(s): Hida A, Yamashita T, Kwak S, et al.
  • Journal Title: Neurology Volume: -
  • Peer Reviewed
• [Journal Article] Autophagy in spinal motor neurons of conditional ADAR2-knockout mice: an implication for a role of calcium in increased autophagy flux in ALS. (2015)
  • Author(s): Sasaki S, Yamashita T, Kwak S
  • Journal Title: Neurosci Lett Volume: 589 Pages: 79-84
  • Peer Reviewed
• [Journal Article] Unique nuclear vacuoles in the motor neurons of conditional ADAR2-knockout mice (2014)
  • Author(s): Sasaki S, Yamashita T, Hideyama T, Kwak S
  • Journal Title: Brain Research Volume: 1550 Pages: 36-46
  • DOI: 10.1016/j.brainres.2014.01.006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients. (2014)
  • Author(s): Yamashita, T., and Kwak, S.
  • Journal Title: Brain Res. Volume: in press. Pages: 28-38
  • DOI: 10.1016/j.brainres.2013.12.011
  • Peer Reviewed / Open Access
• [Journal Article] TDP-43病理形成メカニズム (2014)
  • Author(s): 山下雄也, ＊郭 伸
  • Journal Title: Dementia Japan Volume: 28 Pages: 307-318
• [Journal Article] TDP-43病理形成メカニズムにおけるTDP-43のカルパイン依存性断片化の意義 (2014)
  • Author(s): 山下雄也, ＊郭 伸
  • Journal Title: 臨床神経 Volume: 54 Pages: 1151-1154
  • NAID: 130004921169
• [Presentation] Development of specific therapy for sporadic ALS (2016)
  • Author(s): Shin Kwak
  • Organizer: 3rd World Centenarians Initiative International Symposium on Amyotrophic Lateral Sclerosis
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府豊中市）
  • Year and Date: 2016-02-19
  • Int'l Joint Research / Invited
• [Presentation] A role for inefficient RNA editing in the amyotrophic lateral sclerosis (ALS) pathogenesis (2015)
  • Author(s): Shin Kwak
  • Organizer: 第58回神経科学学会大会 International Society for Neurochemistry/Japanese Society for Neurochemistry Joint Symposium "Epigenetics in neurological and psychiatric diseases
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Year and Date: 2015-09-13
  • Int'l Joint Research / Invited
• [Presentation] AMPA受容体アンタゴニストであるランパネルを用いたALS治療法の開発 (2015)
  • Author(s): 山下雄也, 廣瀬直己, 赤松恵, 寺本さやか, 蔡慧令, 郭伸
  • Organizer: 第58回日本神経科学会大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-07-29
• [Presentation] 分子病態モデルマウスを用いた筋萎縮性側索硬化症の遺伝子治療法開発 (2015)
  • Author(s): 郭 伸
  • Organizer: 第56回日本神経学会学術大会 ランチョンセミナー33「ALS研究と緩和ケアの最前線」
  • Place of Presentation: 新潟コンベンションセンター（新潟県新潟市）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] ALSのALSFRS-Rスコアの経時的変化とアクティグラフによる運動量の検討 (2015)
  • Author(s): 相澤仁志、加藤陽久、郭 伸
  • Organizer: 第56回日本神経学会学術大会 ポスター
  • Place of Presentation: 新潟コンベンションセンター（新潟県新潟市）
  • Year and Date: 2015-05-22
• [Presentation] Mechanism-based gene therapy for sporadic ALS (2015)
  • Author(s): 郭 伸、山下雄也、寺本さやか
  • Organizer: 第56回日本神経学会学術大会 Hot Topics 18 “Gene Therapy for Neurological disorders
  • Place of Presentation: 新潟コンベンションセンター（新潟県新潟市）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] 孤発性ALSの分子病態解析に基づいた治療法の開発 (2015)
  • Author(s): 郭 伸
  • Organizer: 京都大学iPS細胞研究所セミナー
  • Place of Presentation: 京都大学
  • Year and Date: 2015-01-23
• [Presentation] ADAR2-downregulation, a pathogenesis of ALS and a target for therapy (2014)
  • Author(s): Kwak S
  • Organizer: Workshop “RNA editing—from genomic prediction to function
  • Place of Presentation: Ein Gedi, Israel
  • Year and Date: 2014-12-07 – 2014-12-10
• [Presentation] Gene therapy for sporadic ALS using an intravenous injection of AAV vector (2014)
  • Author(s): Yamashita T, Chai HL, Teramoto S, Muramatsu S, Kwak S
  • Organizer: The 25th International Symposium on MND/ALS
  • Place of Presentation: Brussels, Belgium
  • Year and Date: 2014-12-05 – 2014-12-07
• [Presentation] Mechanism-based gene therapy for ALS using sporadic ALS model mice (2014)
  • Author(s): Yamashita T, Chai HL, Teramoto S, Tsuji S, Shimazaki K, Muramatsu S-I, Kwak S
  • Organizer: The 45th Annual Meeting Society for Neuroscience
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] AAV-ADAR2によるALSの遺伝子治療 (2014)
  • Author(s): 郭 伸
  • Organizer: 第36回日本生物学的精神医学会第57回日本神経化学会大会
  • Place of Presentation: 奈良文化会館,奈良
  • Year and Date: 2014-09-29 – 2014-10-01
• [Presentation] Electron microscopic observation of intranuclear aggregation of TDP-43 in mouse cerebral cortex produced by in utero electroporation (2014)
  • Author(s): Akamatsu M, Takuma H, Yamashita T, Okada T, Masu-Keino K, Oehring H, Kwak S, Masu M, Jirikowski FG
  • Organizer: 第37回日本神経科学大会Neuro2014
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 孤発性ALSモデルマウスを用いたALSの遺伝子治療法開発の試み (2014)
  • Author(s): 山下雄也, 蔡 慧玲, 寺本さやか, 辻 省次, 島崎久仁子, 村松慎一, 郭 伸
  • Organizer: 第37回日本神経科学大会Neuro2014
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] ペランパネルはALSモデルマウス運動ニューロンのTDP-43病理を軽減する (2014)
  • Author(s): 蔡 慧玲, 郭 伸, 山下雄也
  • Organizer: 第37回日本神経科学大会Neuro2014
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
• [Presentation] 分子病態モデルマウスを用いた筋萎縮性側索硬化症の遺伝子治療法開発 (2014)
  • Author(s): 郭 伸
  • Organizer: 第5回東京ALSフォーラム
  • Place of Presentation: シェラトン都ホテル東京, 東京
  • Year and Date: 2014-08-23
• [Presentation] ALS 治療への展望 (2014)
  • Author(s): 郭 伸
  • Organizer: 第12回神経難病とケアを考える会,
  • Place of Presentation: エーザイホール, 東京
  • Year and Date: 2014-06-28
  • Invited
• [Presentation] Development of a gene therapy for sporadic ALS by normalizing ADAR2 activity in the motor neurons using a vascular type AAV vector (2014)
  • Author(s): Kwak S, Yamashita T, Chai HL, Teramoto S, Muramatsu S-I
  • Organizer: The 24th Meeting of the European Neurological Society
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 2014-05-31 – 2014-06-03
• [Presentation] 分子病態に基づいた孤発性ALSの遺伝子治療法の開発 (2014)
  • Author(s): 郭 伸, 山下雄也, 蔡 慧玲, 寺本さやか, 辻省次, 島崎久仁子, 村松愼一
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場, 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] 子宮内電気穿孔法TDP-43遺伝子導入によるin vivo形成封入体の微細形態の検討 (2014)
  • Author(s): 詫間 浩, 赤松 恵, 山下雄也, Hartmut Oehring, 岡田拓也, 枡 和子, 石井一弘, Gustav Jirikowsk, 郭 伸, 枡 正幸, 玉岡 晃
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場, 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] AMPA受容体サブユニットGluA2のQ/R部位RNA編集率に対する薬剤の効果 (2014)
  • Author(s): 澤田 潤, 相澤仁志, 浅野目明日香, 高橋佳恵, 斎藤 司, 片山隆行, 山下雄也, 郭 伸, 長谷部直幸
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場, 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Presentation] TDP-43病理形成メカニズムにおけるTDP-43のカルパイン依存性断片化の意義 (2014)
  • Author(s): 山下雄也, 郭 伸
  • Organizer: シンポジウム「TDP43の新展開」第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場, 福岡
  • Year and Date: 2014-05-21 – 2014-05-24
• [Remarks] 東京大学大学院医学系研究科 郭 研究室
  • URL: http://square.umin.ac.jp/teamkwak/
• [Remarks] 東京大学大学院医学系研究科 疾患生命工学センター 臨床医工学部門 郭 研究室
  • URL: http://square.umin.ac.jp/teamkwak/news.html