血管内投与型ＡＡＶベクターによる神経変性疾患の病態解析

• Project Area: Generation of synapse-neurocircuit pathology
• Project/Area Number: 23110515
• 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): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2012: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 神経変性疾患 / 遺伝子治療

Outline of Annual Research Achievements

神経変性疾患の病態解明と遺伝子治療法の開発を目的として研究を実施した. 独自に新規開発した血管内投与により広範な中枢神経領域の神経細胞に効率よく遺伝子を導入できるアデノ随伴ウイルス(AAV)ベクターを応用した. このベクターはマウス・ラットだけでなくカニクイサルなど大型動物の脊髄前角神経細胞にも遺伝子導入できる. 認知症を呈する前頭側頭葉変性症(FTLD)において神経細胞内のユビキチン陽性封入体の成分として同定され, その後, 家族性筋萎縮性側索硬化症(ALS)で遺伝子変異が見いだされたTDP-43は, 神経変性疾患の病態解明の鍵となる分子として注目されている. 本研究では, TDP-43を発現する血管内投与型AAVベクターを応用してモデル動物を作製した. 変異型TDP-43を脳・脊髄の神経細胞で発現さマウスでは運動機能の障害が認められた. また, 神経変性疾患に対する新規遺伝子治療としてAlzheimer病モデルマウスの脳内の広範な領域でAβ分解酵素のNeprilysin を発現させることにより認知機能の改善効果を得た. さらにmiRNAを発現するベクターを作製し, 筋肉・血管・心腔・脊髄腔などから中枢神経内の神経細胞へ送達することに成功した. 球脊髄性筋萎縮症(SBMA)の病態に関連したmiRNAをSBMAモデルマウスの筋肉内に投与することにより, 脊髄の異常アンドロゲン受容体(AR)蛋白の発現を減少させ表現型の改善が得られた.

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [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] 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] 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
• [Journal Article] Gene therapy for aromatic L-amino acid decarboxylase deficiency. (2012)
  • Author(s): Hwu WL, Muramatsu S, Tseng SH, Tzen KY, Lee NC, Chien YH, Snyder RO, Brrne BJ, Tai CH, Wu RM
  • Journal Title: Sci Transl Med Volume: 16;4(134) Issue: 134 Pages: 134-161
  • DOI: 10.1126/scitranslmed.3003640
  • Peer Reviewed
• [Journal Article] Careful clinical observation is essential for diagnosis of Huntington disease. (2012)
  • Author(s): Nakamura K, Ota M, Kawata A, Isozaki E, Muramatsu S, Matsubara S
  • Journal Title: Arq Neuropsiquiatr Volume: 70(8) Pages: 646-646
  • Peer Reviewed
• [Journal Article] Hsp40 Gene Therapy Exerts Therapeutic Effects on Polyglutamine Disease Micevia a Non-Cell Autonomous Mechanism. (2012)
  • Author(s): H. Akiko Popiel
  • Journal Title: PLoS One Volume: 7 Issue: 11 Pages: e51069-e51069
  • DOI: 10.1371/journal.pone.0051069
  • Peer Reviewed
• [Journal Article] Preclinical substantia nigra dysfunction in rapid eye movement sleep behaviour disorder (2012)
  • Author(s): Miyamoto M, Muramatsu S
  • Journal Title: Sleep Med Volume: 13(1) Issue: 1 Pages: 102-106
  • DOI: 10.1016/j.sleep.2011.03.024
  • Peer Reviewed
• [Journal Article] Dopamine release via the vacuolar ATPase V0 sector c-subunit, confirmed in N18 neuroblastoma cells results in behavioral recovery in hemiparkinsonian mice (2012)
  • Author(s): Jin,D., Hashii,M., Higashida,H
  • Journal Title: Neurochem. Int Volume: 61 Issue: 6 Pages: 907-912
  • DOI: 10.1016/j.neuint.2011.12.021
  • NAID: 120004966609
  • Peer Reviewed
• [Journal Article] Subregional 6-[18F]fluoro-L-m-tyrosine uptake in the striatum in Parkinson's disease (2011)
  • Author(s): Asari S, Muramatsu S
  • Journal Title: BMC Neurol Pages: 11-35
  • Peer Reviewed
• [Journal Article] Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection (2011)
  • Author(s): Tokuoka H, Muramatsu S
  • Journal Title: J Biol Chem Volume: 286(50) Pages: 43549-43558
  • Peer Reviewed
• [Presentation] New frontiers in gene therapy of Parkinson Disease. (2013)
  • Author(s): Muramatsu S
  • Organizer: Nuove frontiere nella terapia del Parkinson
  • Place of Presentation: Bari, Italy
  • Year and Date: 2013-02-22
  • Invited
• [Presentation] Parkinson病遺伝子治療の長期効果. Long-term outcomes of gene therapy for Parkinson disease. (2013)
  • Author(s): 村松慎一
  • Organizer: 第52回日本定位・機能神経外科学会
  • Place of Presentation: 岡山
  • Year and Date: 2013-01-19
• [Presentation] AAVベクターによる神経疾患の遺伝子治療. (2012)
  • Author(s): 村松慎一
  • Organizer: 日本薬学界北陸支部 特別講演会
  • Place of Presentation: 富山
  • Year and Date: 2012-11-12
  • Invited
• [Presentation] AADC欠損症の遺伝子治療. (2012)
  • Author(s): 村松慎一
  • Organizer: 日本人類遺伝学会 第57回大会
  • Place of Presentation: 東京
  • Year and Date: 2012-10-26
• [Presentation] パーキンソン病の遺伝子治療におけるＡＡＤＣ遺伝子長期発現. (2012)
  • Author(s): 浅利さやか, 中村優子, 川上忠孝, 池口邦彦, 佐藤俊彦, 村松慎一, 福嶋敬宣, 藤本健一, 中野今治
  • Organizer: Movement Disorder Society Japan第6回学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-13
• [Presentation] Gene therapy for Parkinson’s disease: Progress and current challenges. (2012)
  • Author(s): Muramatsu S
  • Organizer: 2012 Annual meeting of Genetic Epidemiology of Parkinson’s Disease
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2012-10-09
  • Invited
• [Presentation] The differences of the action of shati between the nucleus accumbens and dorsal striatum on the methamphetamine-induced addictive behaviors in mice. (2012)
  • Author(s): Sumi K, Miyamoto Y, Ishikawa Y, Iegaki N, Muramatsu S, Hibi Y, Nabeshima T, Uno K, Nitta A
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry/55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: 神戸
  • Year and Date: 2012-10-02
• [Presentation] Parkinson病の遺伝子治療. (2012)
  • Author(s): 村松慎一
  • Organizer: 第11回日本再生医療学会総会 パネルディスカッション
  • Place of Presentation: 横浜
  • Year and Date: 2012-06-12
• [Presentation] パーキンソン病のすくみ足と青斑核のＦＭＴ－ＰＥＴ解析. (2012)
  • Author(s): 浅利さやか, 村松慎一, 藤本健一, 齋藤順一, 佐藤俊彦, 中野今治
  • Organizer: 第53回日本神経学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2012-05-25
• [Presentation] Gene therapy for Parkinson’s disease. (2012)
  • Author(s): 村松慎一
  • Organizer: 第53回日本神経学会総会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-05-24
• [Presentation] AADC Gene therapy for Parkinson’s disease: results of 3-5 years of follow up. (2012)
  • Author(s): Muramatsu S
  • Organizer: The 15th Annual Meeting of the American Society of Gene Cell Therapy
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2012-05-16
• [Presentation] Gene therapy : the state of the art (2011)
  • Author(s): Muramatsu S
  • Organizer: 6th International Expert Meeting on the Treatment of Parkinson's disease
  • Place of Presentation: 品川プリンスホテル(東京都)
  • Year and Date: 2011-10-30
• [Presentation] Gene therapy for Parkinson's disease : Four years follow-up (2011)
  • Author(s): Muramatsu S
  • Organizer: The 8th Nikko International Symposium
  • Place of Presentation: 自治医科大学(栃木県)
  • Year and Date: 2011-10-21
• [Presentation] パーキンソン病の遺伝子治療 (2011)
  • Author(s): 村松慎一
  • Organizer: 平成23年度第10回自治医科大学シンポジウム
  • Place of Presentation: 自治医科大学(栃木県)
  • Year and Date: 2011-09-02
• [Presentation] In vivo imaging in cell and gene therapy for Parkinson's disease (2011)
  • Author(s): Muramatsu S
  • Organizer: The 17th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 九州大学(福岡県)
  • Year and Date: 2011-07-17
• [Presentation] A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease (2011)
  • Author(s): Muramatsu S
  • Organizer: The 17th Annual Meeting of the Japan Society of Gene Therapy, 2nd Takara Bio Award Lecture
  • Place of Presentation: 九州大学(福岡県)
  • Year and Date: 2011-07-15
• [Presentation] AADC gene therapy for Parkinson's disease : Four years of follow-up (2011)
  • Author(s): Muramatsu S
  • Organizer: The 17th Annual Meeting of the Japan Society of Gene Therapy, Best Presentation
  • Place of Presentation: 九州大学(福岡県)
  • Year and Date: 2011-07-15
• [Presentation] Gene therapy for Parkinson's disease : Strategies for the local production of dopamine (2011)
  • Author(s): Muramatsu S
  • Organizer: The Federation of European Biochemical Societies 36th FEBS Congress
  • Place of Presentation: Centro Congressi Lingotto(イタリア)(招待講演)
  • Year and Date: 2011-06-30
• [Presentation] PET assessment of the aromatic L-amino acid decarboxylase gene expression in a phase I gene therapy study for Parkinson's disease (2011)
  • Author(s): Asari S, Muramatsu S
  • Organizer: 15th International Congress of Parkinson's Disease and Movement Disorders
  • Place of Presentation: Metro Toronto Convention Centre(カナダ)
  • Year and Date: 2011-06-09
• [Presentation] パーキンソン病(PD)の遺伝子治療におけるAADC遺伝子の長期発現 (2011)
  • Author(s): 浅利さやか, 村松慎一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-05-19
• [Presentation] 凝集阻害分子の遺伝子治療によるポリグルタミン病モデルマウスに対する治療効果 (2011)
  • Author(s): ポピェルヘレナ明子, 村松慎一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-05-18
• [Presentation] 血管内投与型AAVベクターによる乏突起膠細胞への遺伝子導入 (2011)
  • Author(s): 村松慎一
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-05-18
• [Book] Assessment of dopaminergic function in Parkinson's disease by SPECT/PET
  • Author(s): Muramatsu S
  • Publisher: Nova Publishers(in press)
• [Book] Gene therapy for continuous dopamine production in Parkinson's disease
  • Author(s): Muramatsu S
  • Publisher: Nova Publishers(in press)
• [Book] Cell therapy for Parkinson's disease
  • Author(s): Kondo Y, Muramatsu S
  • Publisher: Springer-Verlag(in press)