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Gene therapy against Rett syndrome and functional analysis of MeCP2, using blood-brain barrier-penetrating AAV vectors

Research Project

Project/Area Number 18H02521
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 46010:Neuroscience-general-related
Research InstitutionGunma University

Principal Investigator

HIRAI HIROKAZU  群馬大学, 大学院医学系研究科, 教授 (70291086)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Keywords自閉症 / MeCP2 / AAV / レット症候群 / 小脳 / 細胞種特異的プロモーター / Cre / floxマウス / ウイルスベクター / シナプス可塑性 / プルキンエ細胞
Outline of Final Research Achievements

Rett syndrome and MeCP2 duplication syndrome, which are characterized by various manifestations such as autism and epilepsy, are caused by mutation of MeCP2 gene. MeCP2 is critical for brain development in both neurons and astrocytes. In this study, we examined which MeCP2 in neurons or in astrocytes is critical for brain function of mature mice. We found that overexpression of MeCP2 in astrocytes caused no abnormal phenotypes, while overexpression in neurons induced impaired social behavior. In addition, we succeeded to knockout MeCP2 gene from mature mouse cerebellar neurons.

Academic Significance and Societal Importance of the Research Achievements

MeCP2はニューロンとアストロサイトの両方で、脳の発達に重要な役割を果たすことが知られている。しかし、MeCP2は成熟後も脳で発現し続けるが、成熟脳における役割はほとんど明らかになっていない。本研究で、成熟マウスのニューロンにMeCP2を過剰発現させると他のマウスにあまり関心を示さなくなった。すなわち、ニューロンに発現するMeCP2は他者とコミュニケーションをとる社会行動に重要な役割を果たすことが示唆された。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (20 results)

All 2021 2020 2019 2018 Other

All Int'l Joint Research (2 results) Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 11 results,  Open Access: 6 results) Presentation (1 results) (of which Int'l Joint Research: 1 results) Remarks (4 results)

  • [Int'l Joint Research] ミネソタ大学(米国)

    • Related Report
      2019 Annual Research Report
  • [Int'l Joint Research] コペンハーゲン大学(デンマーク)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] GABAergic neuron-specific whole-brain transduction by AAV-PHP.B incorporated with a new GAD65 promoter2021

    • Author(s)
      Hoshino Chiaki、Konno Ayumu、Hosoi Nobutake、Kaneko Ryosuke、Mukai Ryo、Nakai Junichi、Hirai Hirokazu
    • Journal Title

      Molecular Brain

      Volume: 14 Issue: 1 Pages: 1-18

    • DOI

      10.1186/s13041-021-00746-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] BATTLE: Genetically Engineered Strategies for Split-Tunable Allocation of Multiple Transgenes in the Nervous System2020

    • Author(s)
      Kohara Keigo、Inoue Akitoshi、Nakano Yousuke、Hirai Hirokazu、Kobayashi Takuya、Maruyama Masato、Baba Ryosuke、Kawashima Chiho
    • Journal Title

      iScience

      Volume: 23 Issue: 6 Pages: 101248-101248

    • DOI

      10.1016/j.isci.2020.101248

    • NAID

      120006884902

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ataxic phenotype and neurodegeneration are triggered by the impairment of chaperone‐mediated autophagy in cerebellar neurons2020

    • Author(s)
      Sato Masahiro、Ohta Tomoko、Morikawa Yuri、Konno Ayumu、Hirai Hirokazu、Kurauchi Yuki、Hisatsune Akinori、Katsuki Hiroshi、Seki Takahiro
    • Journal Title

      Neuropathology and Applied Neurobiology

      Volume: 47 Issue: 2 Pages: 198-209

    • DOI

      10.1111/nan.12649

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficient whole brain transduction by systemic infusion of minimally purified AAV-PHP.eB2020

    • Author(s)
      Konno Ayumu、Hirai Hirokazu
    • Journal Title

      Journal of Neuroscience Methods

      Volume: 346 Pages: 108914-108914

    • DOI

      10.1016/j.jneumeth.2020.108914

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Protocol for BATTLE-1EX: A High-Resolution Imaging Method to Visualize Whole Synaptic Structures and their Components in the Nervous System2020

    • Author(s)
      Inoue Akitoshi、Kobayashi Takuya、Hirai Hirokazu、Kanaya Noriko、Kohara Keigo
    • Journal Title

      STAR Protocols

      Volume: 1 Issue: 3 Pages: 100166-100166

    • DOI

      10.1016/j.xpro.2020.100166

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Global Knockdown of Retinoid-related Orphan Receptor α in Mature Purkinje Cells Reveals Aberrant Cerebellar Phenotypes of Spinocerebellar Ataxia2020

    • Author(s)
      Yasui Hiroyuki、Matsuzaki Yasunori、Konno Ayumu、Hirai Hirokazu
    • Journal Title

      Neuroscience

      Volume: - Pages: 328-336

    • DOI

      10.1016/j.neuroscience.2020.04.004

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeting inhibitory cerebellar circuitry to alleviate behavioral deficits in a mouse model for studying idiopathic autism2020

    • Author(s)
      Chao Owen Y.、Marron Fernandez de Velasco Ezequiel、Pathak Salil Saurav、Maitra Swati、Zhang Hao、Duvick Lisa、Wickman Kevin、Orr Harry T.、Hirai Hirokazu、Yang Yi-Mei
    • Journal Title

      Neuropsychopharmacology

      Volume: - Issue: 7 Pages: 1159-1170

    • DOI

      10.1038/s41386-020-0656-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Distinct temporal integration of noradrenaline signaling by astrocytic second messengers during vigilance2020

    • Author(s)
      Oe Yuki、Wang Xiaowen、Patriarchi Tommaso、Konno Ayumu、Ozawa Katsuya、Yahagi Kazuko、Hirai Hirokazu、Tian Lin、McHugh Thomas J.、Hirase Hajime
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 471-471

    • DOI

      10.1038/s41467-020-14378-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Advanced CUBIC tissue clearing for whole-organ cell profiling2019

    • Author(s)
      Matsumoto Katsuhiko、Mitani Tomoki T.、Horiguchi Shuhei A.、Kaneshiro Junichi、Murakami Tatsuya C.、Mano Tomoyuki、Fujishima Hiroshi、Konno Ayumu、Watanabe Tomonobu M.、Hirai Hirokazu、Ueda Hiroki R.
    • Journal Title

      Nature Protocols

      Volume: 14 Issue: 12 Pages: 3506-3537

    • DOI

      10.1038/s41596-019-0240-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Neurotropic Properties of AAV-PHP.B Are Shared among Diverse Inbred Strains of Mice2019

    • Author(s)
      Matsuzaki Yasunori、Tanaka Masami、Hakoda Sachiko、Masuda Tatsuki、Miyata Ryota、Konno Ayumu、Hirai Hirokazu
    • Journal Title

      Molecular Therapy

      Volume: 27 Issue: 4 Pages: 700-704

    • DOI

      10.1016/j.ymthe.2019.02.016

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ウイルスベクター経静脈投与による脊髄小脳変性症動物モデルの作出2019

    • Author(s)
      平井宏和
    • Journal Title

      Clinical Neuroscience

      Volume: 37 Pages: 998-1002

    • Related Report
      2019 Annual Research Report
  • [Journal Article] ウイルスベクターの静脈投与によるマウス脳全域への遺伝子導入2019

    • Author(s)
      今野歩, 平井宏和
    • Journal Title

      実験医学

      Volume: 37 Pages: 581-587

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Effects of Neutralizing Antibody Production on AAV-PHP.B-Mediated Transduction of the Mouse Central Nervous System2018

    • Author(s)
      Shinohara Yoichiro、Konno Ayumu、Nitta Keisuke、Matsuzaki Yasunori、Yasui Hiroyuki、Suwa Junya、Hiromura Keiju、Hirai Hirokazu
    • Journal Title

      Molecular Neurobiology

      Volume: - Issue: 6 Pages: 4203-4214

    • DOI

      10.1007/s12035-018-1366-4

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] Mouse strain-dependent BBB (blood-brain barrier) permeability of AAV-PHP.B.2019

    • Author(s)
      Yasunori Matsuzaki, Masami Tanaka, Sachiko Hakoda, Tatsuki Masuda, Ryota Miyata, Ayumu Konno, Hirokazu Hirai
    • Organizer
      FAOPS2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Remarks] アデノ随伴ウイルスベクターを迅速に作製する手法を開発 -遺伝子治療/脳神経科学の基礎研究を加速-

    • URL

      https://www.gunma-u.ac.jp/information/78181

    • Related Report
      2020 Annual Research Report
  • [Remarks] 抑制性ニューロンだけに外来遺伝子を発現させる手法を開発

    • URL

      https://www.gunma-u.ac.jp/information/89316

    • Related Report
      2020 Annual Research Report
  • [Remarks] 群馬大学大学院医学系研究科 脳神経再生医学分野

    • URL

      https://synapse.dept.med.gunma-u.ac.jp/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 群馬大学大学院医学系研究科脳神経再生医学分野

    • URL

      http://synapse.dept.med.gunma-u.ac.jp/

    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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