AAVベクターを応用した神経変性疾患の病態解析

• Project Area: Generation of synapse-neurocircuit pathology
• Project/Area Number: 25110729
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Jichi Medical University
• Principal Investigator: 村松 慎一 自治医科大学, 医学部, 教授 (10239543)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥11,600,000、Indirect Cost: ¥3,480,000); Fiscal Year 2014: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2013: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 筋萎縮性側索硬化症 / 脊髄小脳失調症 / 遺伝子治療 / 神経変性疾患

Outline of Annual Research Achievements

血液脳関門、髄液脳関門を透過して中枢神経系の広範な領域の神経細胞に目的の遺伝子を送達可能な改良型アデノ随伴ウイルス(AAV)ベクターを応用して、神経変性疾患のシナプス病態の解析と新規遺伝子治療法の開発を行った。筋萎縮性側索硬化症（ALS）では、運動ニューロンにおいてRNA編集酵素adenosine deaminase acting on RNA 2 (ADAR2) の発現が低下し、グルタミン酸AMPA受容体のGluA2サブユニットが未編集型となっている。この変化はALSに特異的な分子異常であり運動ニューロン死の原因である。また、１型脊髄小脳失調症（SCA1）では、DNA構造調節蛋白質high-mobility group box 1 (HMGB1) が減少している。これらの知見は、ADAR2あるいはHMGB1の補充が、それぞれALSとSCA1の遺伝子治療の標的となる事を意味する。ADAR2のコンディショナルノックアウトマウスは、家族性ALSのモデルマウスと異なり孤発性ALSの病態をより正確に反映している。ADAR2遺伝子を搭載した改良型AAVベクターをこの分子病態モデルマウスの血管内に投与し、進行性運動機能低下と運動ニューロン死を阻止することに成功した。また、HMGB1遺伝子を搭載した改良型AAVベクターをSCA1病態モデルマウスの髄液腔に投与し運動機能の改善と生存期間の著明な延長を得た。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Knockdown of dopamine D2 receptors in the nucleus accumbens core suppresses methamphetamine-induced behaviors and signal transduction in mice. (2015)
  • Author(s): Miyamoto Yoshiaki, Iida Asako, Muramatsu Shin-Ichi, Nitta Atsumi
  • Journal Title: The international journal of neuropsychopharmacology Volume: 印刷中 Issue: 4 Pages: 1-7
  • DOI: 10.1093/ijnp/pyu038
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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 S., Nabeshima T., Uno K., Nitta A.
  • Journal Title: Int. J. Neuropsychopharmacol. Volume: 17 Issue: 08 Pages: 1-12
  • DOI: 10.1017/s146114571400011x
  • Peer Reviewed / Open Access
• [Journal Article] Intrastriatal gene delivery of GDNF persisitently attenuates methamphetamine self-administration and relapse in mice (2013)
  • Author(s): Yan Y, Miyamoto Y, Nitta A, Muramatsu S, Ozawa K, Yamada K, Nabeshima T
  • Journal Title: Int JNP Volume: 16 Issue: 7 Pages: 1559-1567
  • DOI: 10.1017/s1461145712001575
  • Peer Reviewed
• [Journal Article] Regulation of the dopaminergic system in a murine model of aromatic L-amino acid decarboxylase deficiency (2013)
  • Author(s): Lee, N.-C., Shieh, Y.-D., Chien, Y.-H., Tzen, K.-Y., Yu, I.-S., Chen, P.-W., Hu, M.-H., Hu, M., Muramatsu, S., Ichinose, H., et al.
  • Journal Title: Neurobiology of disease Volume: 52 Pages: 177-90
  • DOI: 10.1016/j.nbd.2012.12.005
  • Peer Reviewed
• [Journal Article] Global brain delivery of neprilysin gene by intravascular administration of AAV vector in mice (2013)
  • Author(s): Iwata N, Sekiguchi M, Hattori Y, Takahashi A, Asai M, Ji B, Higuchi M, Staufenbiel M, Muramatsu S, Saido TC.
  • Journal Title: Scientific Reports Volume: 3 Issue: 1 Pages: 1472-1472
  • DOI: 10.1038/srep01472
  • NAID: 120006985953
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Rescue of amyotrophic lateral sclerosis phenotype in a mouse model by intravenous AAV9-ADAR2 delivery to motor neurons (2013)
  • Author(s): Yamashita T, Chai HL, Teramoto S, Tsuji S, Shimazaki K, Muramatsu S, Kwak S
  • Journal Title: EMBO Mol Med Volume: 5(11) Issue: 11 Pages: 1710-1719
  • DOI: 10.1002/emmm.201302935
  • Peer Reviewed
• [Journal Article] AADC deficiency: occurring in humans, modeled in rodents. (2013)
  • Author(s): Hwu WL, Lee NC, Chien YH, Muramatsu S, Ichinose H
  • Journal Title: Adv Pharmacol Volume: 68 Pages: 273-284
  • DOI: 10.1016/b978-0-12-411512-5.00013-0
  • Peer Reviewed
• [Presentation] 神経変性疾患に対する遺伝子治療開発. (2015)
  • Author(s): 村松慎一
  • Organizer: 平成26年度文部科学省科学研究費補助金「新学術領域研究」シナプス・ニューロサーキットパソロジーの創成 平成26年度冬の班会議
  • Place of Presentation: 強羅
  • Year and Date: 2015-03-01
• [Presentation] FMT-PETによるParkinson 病の病態解析. (2015)
  • Author(s): 小野さやか, 藤本健一, 池口邦彦, 佐藤俊彦, 村松慎一
  • Organizer: 第54回日本定位・機能神経外科学会
  • Place of Presentation: 東京
  • Year and Date: 2015-01-17
• [Presentation] ＡＡＶベクターによる遺伝子治療. (2015)
  • Author(s): 村松慎一
  • Organizer: 第54回日本定位・機能神経外科学会
  • Place of Presentation: 東京
  • Year and Date: 2015-01-16
• [Presentation] Gene therapy for Parkinson Disease. (2014)
  • Author(s): Muramatsu S
  • Organizer: The First Asian Symposium on AADC Deficiency
  • Place of Presentation: Taipei
  • Year and Date: 2014-12-21
  • Invited
• [Presentation] Parkinson病の遺伝子治療. (2014)
  • Author(s): 村松慎一
  • Organizer: 第32回日本神経治療学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-22
  • Invited
• [Presentation] FMT-PETによるパーキンソン病のすくみ足の病態解析. (2014)
  • Author(s): 小野さやか, 藤本健一, 池口邦彦, 佐藤俊彦, 村松慎一
  • Organizer: 第8回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都
  • Year and Date: 2014-10-04
• [Presentation] 遺伝子治療と細胞治療. 神経変性の制御をめざして (2014)
  • Author(s): 村松慎一
  • Organizer: 第8回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都
  • Year and Date: 2014-10-03
• [Presentation] パーキンソン病の遺伝子治療. AAVベクターを応用した神経・精神疾患の病態解明～基礎から臨床まで～ (2014)
  • Author(s): 村松慎一, 新田淳美
  • Organizer: 第57回日本神経化学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2014-10-01
• [Presentation] 大型動物の広範な中枢神経領域に遺伝子導入可能なアデノ随伴ウイルスベクターの開発. (2014)
  • Author(s): 飯田麻子, 滝野直美, 嶋崎久仁子, 伊藤美加, 村松慎一
  • Organizer: 第57回日本神経化学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2014-09-29
• [Presentation] Gene therapy for Parkinson’s disease in Japan: Current status and problems. (2014)
  • Author(s): 村松慎一
  • Organizer: 第55回日本神経学会学術大会シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-22
• [Presentation] Gene therapy clinical trial update for AADC.
  • Author(s): Muramatsu S
  • Organizer: Cell and Gene Therapies for Inherited Metabolic Disease
  • Place of Presentation: London
  • Invited
• [Presentation] パーキンソン病のAADC遺伝子治療：長期効果遺伝子発現の検証.
  • Author(s): 村松慎一
  • Organizer: 第54回日本神経学会学術大会
  • Place of Presentation: 京都
• [Presentation] Overexpression of shati/nat8l in the dorsal striatum affects emotional behaviors via dysfunction of serotonergic neuronal system in mice.
  • Author(s): Miyamoto Y, Iegaki N, Sumi K, Ishikawa Y, Furuta T, Hibi Y, Muramatsu S, Nabeshima T, Uno K, Nitta A
  • Organizer: The 36th Annual Meeting of Japan Neuroscience Society
  • Place of Presentation: 京都
• [Presentation] Widespread transduction of neurons in the primate brain using intrathecal injection of AAV vectors.
  • Author(s): Iida A, Takino N, Miyauchi H, Shibata H, Ono F, Muramatsu S
  • Organizer: The 36th Annual Meeting of Japan Neuroscience Society
  • Place of Presentation: 京都
• [Presentation] Distinct regulation mechanism of the dopamine content in the striatum from that in the midbrain.
  • Author(s): Iwashita Y, Tokuoka H, Munezane H, Muramatsu S, Ichinose H
  • Organizer: The 36th Annual Meeting of Japan Neuroscience Society
  • Place of Presentation: 京都
• [Presentation] Different effects of shati/nat8l-overexpression on the responses to methamphetamine between in mice nucleus accumbens and dorsal striatum.
  • Author(s): Nitta A, Ishikawa Y, Iegaki Y, Sumi K, Hurukawa-Hibi Y, Muramatsu S, Nabeshima T, Uno K, Miyamoto Y
  • Organizer: The 36th Annual Meeting of Japan Neuroscience Society
  • Place of Presentation: 京都
• [Presentation] Widespread neuronal transduction in the primate brain via intrathecal administration of adeno-associated virus vectors.
  • Author(s): Iida A, Takino N, Miyauchi H, Shibata H, Ono F, Muramatsu S:
  • Organizer: The 19th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 岡山
• [Presentation] Global and effective gene delinery of neprilysin to the brain via intravascular administration of AAV vector in alzheimer’s disease mice.
  • Author(s): Iwata N, Sekiguchi M, Hattori Y, Takahashi A, Asai M, Ji B, Higuchi M, Muramatsu S, Saido TC
  • Organizer: The 19th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 岡山
• [Presentation] 多系統萎縮症(NSA-P)のFMT-PET解析.
  • Author(s): 小野さやか, 藤本健一, 池口邦彦, 村松慎一, 中野今治
  • Organizer: Movement Disorder Society Japan第7回学術集会
  • Place of Presentation: 東京
• [Presentation] Parkinson病に対する遺伝子治療の現状と課題.
  • Author(s): 村松慎一
  • Organizer: 第53回日本定位・機能神経外科学会 シンポジウム
  • Place of Presentation: 大阪
• [Book] Cell therapy for Parkinson's disease. Clinical implications of fetal transplantation in Medicine. (2013)
  • Author(s): Kondo Y, Okuno T, Asari S, Muramatsu S
  • Total Pages: 11
  • Publisher: Springer-Verlag
• [Book] パーキンソン病の遺伝子治療・細胞移植, アクチュアル 脳・神経疾患の臨床 パーキンソン病と運動異常 (2013)
  • Author(s): 村松慎一
  • Total Pages: 8
  • Publisher: 中山書店