Novel therapeutic approaches using the delivery of specific miRNAs for polyglutamine diseases

• Project/Area Number: 23390231
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: ADACHI Hiroaki 名古屋大学, 医学(系)研究科(研究院), 寄附講座准教授 (40432257)
• Co-Investigator(Kenkyū-buntansha): SOBUE Gen 名古屋大学, 医学系研究科, 教授 (20148315) ; KOIKE Haruki 名古屋大学, 医学部附属病院, 病院講師 (80378174) ; TANAKA Fumiaki 横浜市立大学, 医学系研究科, 教授 (30378012)
• Research Collaborator: MIYAZAKI Yu 名古屋大学, 医学系研究科, 客員研究者
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000); Fiscal Year 2013: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 球脊髄性筋萎縮症 / アンドロゲンレセプター / CAGリピート / miRNA / CELF2 / 運動ニューロン病 / 神経変性疾患 / miR-196a / ポリグルタミン病 / Dicer / AAVベクター / アンドロゲン受容体 / トランスジェニックマウス

Research Abstract

Spinal and bulbar muscular atrophy (SBMA) is an inherited neurodegenerative disorder caused by the expansion of the polyglutamine (polyQ) tract of the androgen receptor. Recent functional studies have shown the potent activity of specific miRNAs as disease modifiers both in vitro and in vivo. Thus, potential therapeutic approaches that target the miRNA processing pathway have recently attracted attention. We demonstrated a novel therapeutic approach using the adeno-associated virus (AAV) vector;mediated delivery of a specific miRNA for SBMA. We found that miR-196a enhanced the decay of the AR mRNA by silencing CUGBP, Elav-like family member 2 (CELF2). CELF2 directly acted on AR mRNA and enhanced the stability of AR mRNA. Furthermore, we found that the early intervention of miR-196a delivered by an AAV vector ameliorated the SBMA phenotypes in a mouse model. Our results establish the proof of principle that disease-specific miRNA delivery could be useful in neurodegenerative diseases.

Research Products

• [Journal Article] Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease (2013)
  • Author(s): Qiang Q, Adachi H, Huang Z, Jiang YM, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Tohnai G, Sobue G
  • Journal Title: J Neurochem Volume: 126 Issue: 1 Pages: 122-130
  • DOI: 10.1111/jnc.12172
  • Peer Reviewed
• [Journal Article] p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model (2013)
  • Author(s): Doi H, Adachi H, Katsuno M, Minamiyama M, Matsumoto S, Kondo N, Miyazaki Y, IidaM,Tohnai G, Qiang Q, Tanaka F, Yanagawa T, WarabiE,Ishii T, Sobue G
  • Journal Title: J Neurosci Volume: 33 Issue: 18 Pages: 7710-7727
  • DOI: 10.1523/jneurosci.3021-12.2013
  • Peer Reviewed
• [Journal Article] Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2 (2012)
  • Author(s): Miyazaki Y, Adachi H, Katsuno M, Minamiyama M, Jiang YM, Huang Z, Doi H, Matsumoto S, Kondo N, Iida M, Tohnai G, Tanaka F, Muramatsu S, Sobue G
  • Journal Title: Nat Med Volume: 18 Issue: 7 Pages: 1136-1141
  • DOI: 10.1038/nm.2791
  • Peer Reviewed
• [Presentation] miR-196aはCELF2の発現抑制を介しSBMAの表現型を有意に改善する (2013)
  • Author(s): 宮崎雄, 足立弘明 , 勝野雅央, 村松慎一, 祖父江元
  • Organizer: 第54回日本神経学会総会, 東京都千代田区
  • Place of Presentation: 東京国際フォーラム
  • Year and Date: 2013-05-31
• [Presentation] miR-196aはCELF2の発現抑制を介しSBMAの表現型を有意に改善する (2013)
  • Author(s): 宮崎 雄, 足立弘明, 勝野雅央, 村松慎一, 祖父江 元
  • Organizer: 第54回日本神経学会総会
  • Place of Presentation: 東京都千代田区 (東京国際フォーラム)
• [Presentation] Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2 (2012)
  • Author(s): Miyazaki Y, Adachi H, Katsuno M, Tanaka F, Muramatsu S, Sobue G
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans
  • Year and Date: 2012-10-16
• [Presentation] miR-196aはSBMAにおいて異常ARmRNAの不安定化を促進し表現型を有意に改善させる (2012)
  • Author(s): 宮崎雄, 足立弘明, 勝野雅央, 南山誠, 蒋月梅, 土井英樹, 松本慎二郎, 近藤直英, 飯田円, 藤内玄規, 田中章景, 村松慎一, 祖父江元
  • Organizer: 第53回日本神経学会総会
  • Place of Presentation: 東京千代田区(東京国際フォーラム)
  • Year and Date: 2012-05-24
• [Presentation] miR-196aはSBMAにおいて異常AR mRNAの不安定化を促進し表現型を有意に改善させる (2012)
  • Author(s): 宮崎 雄
  • Organizer: 日本神経学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京）
• [Book] 球脊髄性筋萎縮症に対する分子標的治療法の開発.すべてがわかるALS・運動ニューロン疾患辻省次, 祖父江元編 (2013)
  • Author(s): 勝野雅央, 足立弘明, 祖父江元
  • Publisher: 中山書店
• [Book] すべてがわかるALS・運動ニューロン疾患 (2013)
  • Author(s): 勝野雅央、足立弘明、祖父江 元
  • Total Pages: 384
  • Publisher: 中山書店
• [Remarks]
  • URL: http://www.med.nagoya-u.ac.jp/neurology/research/index.html
• [Remarks] ポリグルタミン病の病態解明と治療法の開発
  • URL: http://www.med.nagoya-u.ac.jp/neurology/research/index.html