Gene therapy for neurodegenerative diseases using modified AAV vectors.

• Project/Area Number: 26293213
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Jichi Medical University
• Principal Investigator: MURAMATSU Shin-ichi 自治医科大学, 医学部, 教授 (10239543)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
• Keywords: 遺伝子治療 / 脊髄小脳失調症 / パーキンソン病 / AAVベクター / アデノ随伴ウイルス / 脳神経疾患 / 認知症

Outline of Final Research Achievements

Using modified adeno-associated virus (AAV) vectors that can delivery therapeutic genes to neurons in broad areas of the central nervous system, we have developed gene therapy for neurodegenerative diseases. Spinocerebellar ataxia type 6 (SCA6) is caused by a polyglutamine repeat expansion within a second CACNA1A gene product, α1ACT. As a potential therapy, the complete silencing of CACNA1A gene expression would be lethal, although the selective elimination of α1ACT protein could be a viable strategy. AAV vector-mediated delivery of miR-3191-5p into the ventricles protected from the Purkinje cell degeneration and ataxia in a mouse model that was made by intraventricular infusion of AAV vector expressing expanded polyglutamine repeats in the α1ACT gene. We also confirmed that transgenes were expressed even after 15 years in a monkey model of Parkinson disease.

Research Products

• [Int'l Joint Research] シカゴ大学(米国)
• [Journal Article] Evaluation of 6-11C-methyl-m-tyrosine as a PET probe for presynaptic dopaminergic activity: a comparison PET study with β-11C-L-DOPA and 18F-FDOPA in Parkinson disease monkeys. (2016)
  • Author(s): Kanazawa M, Ohba H, Harada N, Kakiuchi T, Muramatsu S and Tsukada H
  • Journal Title: J Nucl Med Volume: 57(2) Issue: 2 Pages: 303-308
  • DOI: 10.2967/jnumed.115.161802
  • Peer Reviewed
• [Journal Article] Freezing of Gait in Parkinson's Disease Is Associated with Reduced 6-[18F]Fluoro-L-m-tyrosine Uptake in the Locus Coeruleus (2016)
  • Author(s): Sayaka Asari-Ono
  • Journal Title: Parkinson's Disease Volume: 2016 Pages: 0-5
  • DOI: 10.1155/2016/5430920
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A Novel Reporter Rat Strain That Conditionally Expresses the Bright Red Fluorescent Protein tdTomato. (2016)
  • Author(s): Igarashi H, Koizumi K, Kaneko R, Ikeda K, Egawa R, Yanagawa Y, Muramatsu S, Onimaru H, Ishizuka T, Yawo H.
  • Journal Title: PLoS One. Volume: 11 Issue: 5 Pages: e0155687-e0155687
  • DOI: 10.1371/journal.pone.0155687
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Neurotransmitter release: vacuolar ATPase V0 sector c-subunits in possible gene or cell therapies for Parkinson's, Alzheimer's, and psychiatric diseases. (2016)
  • Author(s): Higashida H, Yokoyama S, Tsuji C and Muramatsu S
  • Journal Title: J Physiol Sci Volume: 67(1) Issue: 1 Pages: 11-17
  • DOI: 10.1007/s12576-016-0462-3
  • NAID: 120005971993
  • Peer Reviewed
• [Journal Article] A miRNA-mediated therapy for SCA6 blocks IRES-driven translation of the CACNA1A second cistron. (2016)
  • Author(s): Miyazaki Y, Du X, Muramatsu S and Gomez C M
  • Journal Title: Sci Transl Med Volume: 8(347) Issue: 347
  • DOI: 10.1126/scitranslmed.aaf5660
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RpA1 ameliorates symptoms of mutant Ataxin-1 knock-in mice and enhances DNA damage repair (2016)
  • Author(s): Taniguchi, JB., Kondo, K., Fujita, K., Chen, X., Homma, H., Sudo, T., Mao, Y., Watase, K., Tanaka, T., Tagawa, K., Tamura, T., Muramatsu, SI., Okazawa, H.
  • Journal Title: Human Molecular Genetics Volume: 25 Pages: 4432-4447
  • DOI: 10.1093/hmg/ddw272
  • Peer Reviewed
• [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] Benefits of neuronal preferential systemic gene therapy for neurotransmitter deficiency. (2015)
  • Author(s): Lee NC, Muramatsu S, Chien YH, Liu WS, Wang WH, Cheng CH, Hu MK, Chen PW, Tzen KY, Byrne BJ and Hwu WL
  • Journal Title: Mol Ther Volume: 23(10) Issue: 10 Pages: 1572-1581
  • DOI: 10.1038/mt.2015.122
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mutational and functional analysis of Glucose transporter I deficiency syndrome. (2015)
  • Author(s): Nakamura S, Osaka H, Muramatsu S, Aoki S, Jimbo EF and Yamagata T
  • Journal Title: Mol Genet Metab Volume: 116(3) Issue: 3 Pages: 157-162
  • DOI: 10.1016/j.ymgme.2015.08.006
  • Peer Reviewed
• [Journal Article] Na,K-ATPaseα3 is a death target of alzheimer patient amyloid-β assembly. (2015)
  • Author(s): Ohnishi T, ..., Matsui K, ..., Hoshi M （計35名, 記載欄不足）
  • Journal Title: Proc Natl Acad Sci U S A Volume: 112 Issue: 32 Pages: 4465-4474
  • DOI: 10.1073/pnas.1421182112
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Induction of neuronal axon outgrowth by Shati/Nat8l by energy metabolism in mice cultured neurons. (2015)
  • Author(s): Sumi K, Uno K, Matsumura S, Miyamoto Y, Furukawa-Hibi Y, Muramatsu S, Nabeshima T, Nitta A.
  • Journal Title: Neuroreport Volume: 26(13) Issue: 13 Pages: 740-746
  • DOI: 10.1097/wnr.0000000000000416
  • Peer Reviewed / Int'l Joint Research
• [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] 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] HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. (2014)
  • Author(s): Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu SI and Okazawa H
  • Journal Title: EMBO Mol Med Volume: 7(1) Pages: 78-101
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] FMT-PETによる芳香族アミノ酸脱炭酸酵素(AADC)欠損症に対する定位脳遺伝子治療の評価. (2017)
  • Author(s): 大貫良幸, 小野さやか, 中嶋剛, 小島華林, 斎藤順一, 多賀直行, 渡辺英寿, 小澤敬也, 佐藤俊彦, 平井真洋, 小坂仁, 川合健介, 山形崇倫, 村松慎一
  • Organizer: 第56回日本定位・機能神経外科学会
  • Place of Presentation: 大阪(コングレコンベンションセンター)
  • Year and Date: 2017-01-28
• [Presentation] Gene therapy for neurodegenerative diseases. (2016)
  • Author(s): Muramatsu S
  • Organizer: European Society of Gene & Therapy
  • Place of Presentation: Florence(Palazzo dei Congressi e Palazzo degli Affari))
  • Year and Date: 2016-10-19
  • Int'l Joint Research / Invited
• [Presentation] パーキンソン病にウイルスベクターを用いた遺伝子治療は可能か－YES. (2016)
  • Author(s): 村松慎一
  • Organizer: 第10回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 京都(京都ホテルオークラ)
  • Year and Date: 2016-10-07
• [Presentation] Gene therapy for central nervous system disorders. (2016)
  • Author(s): Muramatsu S
  • Organizer: The 22th Annual Meeting of the Japan Society of Gene and Cell Therapy
  • Place of Presentation: 東京(虎ノ門ヒルズフォーラム)
  • Year and Date: 2016-07-29
  • Invited
• [Presentation] Gene therapy for AADC deficiency: toward a standard therapy. (2016)
  • Author(s): Hwu WL, Chien YH, Lee NC, Tseng SH, Muramatsu S and Byrne B
  • Organizer: The 22th Annual Meeting of the Japan Society of Gene and Cell Therapy
  • Place of Presentation: 東京(虎ノ門ヒルズフォーラム)
  • Year and Date: 2016-07-28
• [Presentation] Improved motor and cognitive function of Aromatic L-Amino acid Decarboxylase(AADC) deficient patients following gene therapy using the AAV2 vector. (2016)
  • Author(s): Kojima K, Miyauchi A, Nakajima T, Asari-Ono S, Saga Y, Mizukami H, Sato T, Muramatsu S, Osaka H and Yamagata T
  • Organizer: The 22th Annual Meeting of the Japan Society of Gene and Cell Therapy
  • Place of Presentation: 東京(虎ノ門ヒルズフォーラム)
  • Year and Date: 2016-07-28
• [Presentation] Gene therapy for a mouse model of glucose transporter-1 deficiency syndrome. (2016)
  • Author(s): Nakamura S, Osaka H, Muramatsu S, Takino N, Aoki S, F.Jimbo E, Shimazaki K, Onaka T, Ohtsuki S, Terasaki T and Yamagata T
  • Organizer: The 22th Annual Meeting of the Japan Society of Gene and Cell Therapy
  • Place of Presentation: 東京(虎ノ門ヒルズフォーラム)
  • Year and Date: 2016-07-28
• [Presentation] Development and clinical application of gene therapy using AAV for child neurological diseases. (2016)
  • Author(s): Yamagata T, Kojima K, Nakajima T, Miyauchi A, Mizukami H, Osaka H and Muramatsu S
  • Organizer: The 22th Annual Meeting of the Japan Society of Gene and Cell Therapy
  • Place of Presentation: 東京(虎ノ門ヒルズフォーラム)
  • Year and Date: 2016-07-28
• [Presentation] 神経疾患の遺伝子治療. (2016)
  • Author(s): 村松慎一
  • Organizer: 平成28年度日本生化学会関東支部例会
  • Place of Presentation: 下野市(自治医科大学)
  • Year and Date: 2016-06-11
  • Invited
• [Presentation] In vivo monitoring of AADC gene delivery by PET. (2016)
  • Author(s): Muramatsu S
  • Organizer: 57th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 神戸(神戸コンベンションセンター)
  • Year and Date: 2016-05-19
• [Presentation] The second clinical study on AADC Gene Therapy for Parkinson’s Disease. (2016)
  • Author(s): Ando Y, Asari-Ono S, Nakajima T, Watanabe K, Saga Y, Mizukami H, Watanabe E, Sato T, Ozawa K and Muramatsu S
  • Organizer: 57th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 神戸(神戸コンベンションセンター)
  • Year and Date: 2016-05-19
• [Presentation] FMT-PET analysis in gene therapy for AADC deficiency. (2016)
  • Author(s): Asari-Ono S, Nakajima T, Kojima K, Miyauchi A, Saitou J, Saga Y, Mizukami H, Taga N, Takeuchi M, Watanabe E, Ozawa K, Sato T, Kato M, Osaka H, Yamagata T and Muramatsu S
  • Organizer: 57th Annual Meeting of the Japanese Society of Neurology
  • Place of Presentation: 神戸(神戸コンベンションセンター)
  • Year and Date: 2016-05-18
• [Presentation] Gene Therapy for AADC Deficiency - clinical study in Japan. (2016)
  • Author(s): Muramatsu S
  • Organizer: 3rd International AADC 2-day Medical & Scientific Conference
  • Place of Presentation: London(The Lingfield Park Marriott Hotel & Country Club)
  • Year and Date: 2016-05-14
  • Int'l Joint Research / Invited
• [Presentation] AADC欠損症に対する遺伝子治療. (2016)
  • Author(s): 山形崇倫, 小島華林, 宮内彰彦, 多賀直行, 小野さやか, 斎藤順一, 嵯峨泰, 水上浩明, 加藤光広, 中嶋剛, 小坂仁, 村松慎一
  • Organizer: 第15回日本再生医療学会総会 シンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2016-03-18
• [Presentation] 定位的脳手術を用いたAADC欠損症に対する遺伝子治療臨床研究—遺伝子工学と機能神経外科の融合—. (2016)
  • Author(s): 小島華林, 村松慎一, 宮内彰彦, 小野さやか, 多賀直行, 水上浩明, 小坂仁, 山形崇倫, 中嶋剛
  • Organizer: 第56回日本神経学会学術大会 教育講演
  • Place of Presentation: 仙台
  • Year and Date: 2016-01-23
• [Presentation] 神経疾患の遺伝子治療. (2015)
  • Author(s): 村松慎一
  • Organizer: 第57回日本先天代謝異常学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2015-11-12
  • Invited
• [Presentation] Gene therapy for Neurodegenerative Diseases. (2015)
  • Author(s): Muramatsu S
  • Organizer: The 21th Annual Meeting of the Japan Society of Gene Therapy
  • Place of Presentation: 大阪
  • Year and Date: 2015-07-25
• [Presentation] パーキンソン病における軽度認知機能障害と線条体AADC機能解析. (2015)
  • Author(s): 小野さやか, 藤本健一, 川合耕一郎, 齋藤順一, 佐藤俊彦, 村松慎一
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-23
• [Presentation] Parkinson病の細胞移植ー;歴史. (2015)
  • Author(s): 村松慎一
  • Organizer: 第56回日本神経学会学術大会 教育講演
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21
• [Presentation] FMT-PETによるParkinson 病の病態解析. (2015)
  • Author(s): 小野さやか,東京 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’s disease: Current status and challenges. (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
• [Patent(Industrial Property Rights)] てんかん治療のためのアデノ随伴ウイルスビリオン (2016)
  • Inventor(s): 村松慎一、小黒恵司、島崎久仁子
  • Industrial Property Rights Holder: 村松慎一、小黒恵司、島崎久仁子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-01-15