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A novel cell transplantation therapy for ALS using scFv-secreting OPCs

Research Project

Project/Area Number 19H03573
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionShiga University of Medical Science

Principal Investigator

Urushitani Makoto  滋賀医科大学, 医学部, 教授 (60332326)

Co-Investigator(Kenkyū-buntansha) 朝長 啓造  京都大学, ウイルス・再生医科学研究所, 教授 (10301920)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
Fiscal Year 2021: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords筋萎縮性側索硬化症 / 抗体 / SOD1 / 移植 / ウイルスベクター / オリゴデンドロサイト前駆細胞 / オリゴデンドロサイト前駆細胞(OPC) / 再生 / scFv / 細胞間伝搬 / 一本鎖抗体(scFv) / 細胞移植治療 / superoxide dismutase 1
Outline of Research at the Start

我々はOLGの機能改善が新たなALSの治療になるとの仮説に基づき、変異SOD1トランスジェニック(Tg)ラットに対するオリゴデンドロサイト前駆細胞(OPC)の髄腔内移植を行ったところ、長期の生着と有意な延命効果を示すデータが得られている。本研究は、ALS病態におけるOLGの分子病態の解明とOPC移植治療法の確立、さらに細胞移植治療の壁として常に問題となるALS関連蛋白質の細胞間伝搬を「特異的一本鎖抗体を分泌するOPCの移植」によって阻止するというあらたな治療パラダイムの構築を目指すものである。

Outline of Final Research Achievements

Genetic mutations in SOD1 are the most prevalent familial ALS cause in Japan. We designed novel regenerative immunotherapy in which scFv from D3-1 hybridoma mRNA was subcloned into a Bornavirus disease vector (BoDV) to be introduced into oligodendrocytes precursor cells (OPCs-D3-1). We generated a monoclonal antibody against misfolded SOD1, named D3-1. First, we confirmed that intrathecal infusion of full-length D3-1 antibody into H46R SOD1 transgenic rats extended the longevity. Then we injected OPC-D3-1, OPC alone, and saline as procedural control into the cisterna magna of H46R SOD1 rats. Intracysternal transplantation of OPC-D3-1 markedly slowed progression and prevented the worsening of limb functions. Moreover, we observe marked amelioration of motor neuron loss and gliosis and reduction of neuromuscular junctions. Mutant SOD1 proteins were also reduced in the spinal cords. Transcriptome analyses demonstrated the downregulation of proinflammatory molecules.

Academic Significance and Societal Importance of the Research Achievements

遺伝子疾患に対する核酸治療の開発が進み、難病の治療展望に明るい光が見えてきました。我々の研究成果は変異遺伝子が作り出す蛋白質を治療標的と捉え、これまでの抗体治療の限界を細胞移植という全く異なる次元の治療法と融合させることによって、難病ALSに新しい治療の選択肢を提示しました。特に腫瘍原性や炎症を起こしにくいオリゴデンドロサイトを用いた抗体再生治療は世界初の成果です。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (39 results)

All 2022 2021 2020 2019

All Journal Article (20 results) (of which Peer Reviewed: 15 results,  Open Access: 4 results) Presentation (13 results) (of which Int'l Joint Research: 4 results,  Invited: 7 results) Book (3 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro2022

    • Author(s)
      Asada-Utsugi Megumi、Uemura Kengo、Ayaki Takashi、T. Uemura Maiko、Minamiyama Sumio、Hikiami Ryota、Morimura Toshifumi、Shodai Akemi、Ueki Takatoshi、Takahashi Ryosuke、Kinoshita Ayae、Urushitani Makoto
    • Journal Title

      Communications Biology

      Volume: 5 Issue: 1 Pages: 00-00

    • DOI

      10.1038/s42003-022-03312-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bone marrow-derived inducible microglia-like cells ameliorate motor function and survival in a mouse model of amyotrophic lateral sclerosis2022

    • Author(s)
      Kobashi Shuhei、Terashima Tomoya、Katagi Miwako、Urushitani Makoto、Kojima Hideto
    • Journal Title

      Cytotherapy

      Volume: 00 Issue: 8 Pages: 00-00

    • DOI

      10.1016/j.jcyt.2022.02.001

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The inhibitory effects of MIF on accumulation of canine degenerative myelopathy-associated mutant SOD1 aggregation2022

    • Author(s)
      Nomura Saki、Kobatake Yui、Takashima Satoshi、Kamishina Hiroaki、Urushitani Makoto、Nishii Naohito
    • Journal Title

      Research in Veterinary Science

      Volume: 147 Pages: 7-11

    • DOI

      10.1016/j.rvsc.2022.03.013

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Spinal Muscular Atrophy Type 3 Showing a Specific Pattern of Selective Vulnerability on Muscle Ultrasound2021

    • Author(s)
      Nakamura Ryutaro、Kitamura Akihiro、Tsukamoto Takahito、Otowa Yuhei、Okamoto Naoki、Ogawa Nobuhiro、Yamakawa Isamu、Kim Hyoh、Sanada Mitsuru、Urushitani Makoto
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 12 Pages: 1935-1939

    • DOI

      10.2169/internalmedicine.6396-20

    • NAID

      130008052661

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-06-15
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Effect of Intravenous Methylprednisolone on Recurrent Exacerbation in Hematologic Malignancy-associated Progressive Multifocal Leukoencephalopathy2021

    • Author(s)
      Nakamura Ryutaro、Kitamura Akihiro、Tsukamoto Takahito、Tamura Ryota、Ogawa Nobuhiro、Yamakawa Isamu、Kim Hyoh、Kawai Michihiro、Sanada Mitsuru、Urushitani Makoto
    • Journal Title

      Internal Medicine

      Volume: 60 Issue: 8 Pages: 1287-1291

    • DOI

      10.2169/internalmedicine.5917-20

    • NAID

      130008025059

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2021-04-15
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vitro evidence of propagation of superoxide dismutase-1 protein aggregation in canine degenerative myelopathy2021

    • Author(s)
      Tanaka N.、Kimura S.、Kamatari Y.O.、Nakata K.、Kobatake Y.、Inden M.、Yamato O.、Urushitani M.、Maeda S.、Kamishina H.
    • Journal Title

      The Veterinary Journal

      Volume: 274 Pages: 105710-105710

    • DOI

      10.1016/j.tvjl.2021.105710

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks2021

    • Author(s)
      M. Asada-Utsugi, K. Uemura, M. Kubota, Y. Noda, Y. Tashiro, T. M. Uemura, H. Yamakado, M. Urushitani, R. Takahashi, S. Hattori, T. Miyakawa, N. Ageta-Ishihara, K. Kobayashi, M. Kinoshita, A. Kinoshita
    • Journal Title

      Molecular Brain

      Volume: 14 Issue: 1 Pages: 23-23

    • DOI

      10.1186/s13041-021-00738-1

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Short-Term Effect of Intensive Speech Therapy on Dysarthria in Patients With Sporadic Spinocerebellar Degeneration2021

    • Author(s)
      Sonoda Yuma、Yoshida Nao、Kawami Kazunori、Kitamura Akihiro、Ogawa Nobuhiro、Yamakawa Isamu、Kim Hyoh、Sanada Mitsuru、Imai Shinji、Urushitani Makoto
    • Journal Title

      Journal of Speech, Language, and Hearing Research

      Volume: 64 Issue: 3 Pages: 725-733

    • DOI

      10.1044/2020_jslhr-20-00259

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Amelioration of motor and nonmotor symptoms in cortical cerebellar atrophy and multiple system atrophy-cerebellar type by inpatient rehabilitation2021

    • Author(s)
      Sonoda Yuma、Yamanaka Yuya、Sawano Shinichiro、Komada Ryo、Kugo Masato、Kitamura Akihiro、Ogawa Nobuhiro、Yamakawa Isamu、Kim Hyoh、Sanada Mitsuru、Imai Shinji、Urushitani Makoto
    • Journal Title

      International Journal of Rehabilitation Research

      Volume: Publish Ahead of Print Issue: 2 Pages: 00-00

    • DOI

      10.1097/mrr.0000000000000455

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Up-regulated spinal microRNAs induce aggregation of superoxide dismutase 1 protein in canine degenerative myelopathy2021

    • Author(s)
      Nakata Kohei、Namiki Mariko、Kobatake Yui、Nishida Hidetaka、Sakai Hiroki、Yamato Osamu、Urushitani Makoto、Maeda Sadatoshi、Kamishina Hiroaki
    • Journal Title

      Research in Veterinary Science

      Volume: 135 Pages: 479-485

    • DOI

      10.1016/j.rvsc.2020.11.018

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Accumulation of HAX-1 and PARL in brainstem- and cortical-type Lewy bodies in Parkinson's disease and dementia with Lewy bodies2020

    • Author(s)
      Kawamoto Yasuhiro、Ayaki Takashi、Urushitani Makoto、Ito Hidefumi、Takahashi Ryosuke
    • Journal Title

      Journal of the Neurological Sciences

      Volume: 415 Pages: 116928-116928

    • DOI

      10.1016/j.jns.2020.116928

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Transplantation of M2-deviated microglia promotes recovery of motor function after spinal cord injury in mice.2020

    • Author(s)
      Kobashi S, Terashima T, Miwako Katagi, Yuki Nakae, Junko Okano, Yoshihisa Suzuki, Makoto Urushitani, Hideto Kojima.
    • Journal Title

      Molecular Therapy

      Volume: 28 Issue: 1 Pages: 254-265

    • DOI

      10.1016/j.ymthe.2019.09.004

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 筋萎縮性側索硬化症 プロテイノパチーの観点から2020

    • Author(s)
      引網 亮太, 南山 素三雄, 漆谷 真
    • Journal Title

      医学のあゆみ

      Volume: 273 Pages: 44-49

    • Related Report
      2020 Annual Research Report
  • [Journal Article] 筋萎縮性側索硬化症における創薬開発の現状と展望2020

    • Author(s)
      漆谷 真
    • Journal Title

      BRAIN and NERVE

      Volume: 61 Pages: 81-87

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Myositis with sarcoplasmic inclusions in Nakajo‐Nishimura syndrome: a genetic inflammatory myopathy2020

    • Author(s)
      Takashi Ayaki、Kenya Murata、Kanazawa Nobuo、Akinori Uruha、Koichiro Ohmura、Kazuma Sugie、Shimpei Kasagi、Fangzhou Li、Megumi Mori、Nakajima Ran、Sasai Tsuneo、Nishino Ichizo、Satoshi Ueno、Makoto Urushitani、Fukumi Furukawa、Ito Hidefumi、Takahashi Ryosuke
    • Journal Title

      Neuropathology and Applied Neurobiology

      Volume: 00 Issue: 6 Pages: 00-00

    • DOI

      10.1111/nan.12614

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Propofol infusion syndrome complicated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes: a case report2019

    • Author(s)
      Shimizu Junji、Tabata Takahisa、Tsujita Yasuyuki、Yamane Tetsunobu、Yamamoto Yutaka、Tsukamoto Takahito、Ogawa Nobuhiro、Kim Hyou、Urushitani Makoto、Eguchi Yutaka
    • Journal Title

      Acute Medicine & Surgery

      Volume: 7 Issue: 1 Pages: 00-00

    • DOI

      10.1002/ams2.473

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Thigh muscle MRI findings in myopathy associated with anti‐mitochondrial antibody2019

    • Author(s)
      Minamiyama Sumio、Ueda Sakiho、Nakashima Ran、Yamakado Hodaka、Sakato Yusuke、Yamashita Hirofumi、Sawamoto Nobukatsu、Fujimoto Ryota、Nishino Ichizo、Urushitani Makoto、Mimori Tsuneyo、Takahashi Ryosuke
    • Journal Title

      Muscle & Nerve

      Volume: 61 Issue: 1 Pages: 81-87

    • DOI

      10.1002/mus.26731

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 運動ニューロン疾患の抗体を用いた治療開発の展望2019

    • Author(s)
      玉木 良高,漆谷 真
    • Journal Title

      脳神経内科

      Volume: 90 Pages: 137-145

    • Related Report
      2019 Annual Research Report
  • [Journal Article] ALSにおける免疫療法開発の現状と展 望.特集「ALS2019」2019

    • Author(s)
      漆谷 真,玉木 良高,引網 亮太,南山 素三雄
    • Journal Title

      BRAIN and NERVE

      Volume: 7 Pages: 1289-1301

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 筋萎縮性側索硬化症に対する創薬開発の現状と展望「神経難病をクスリで治 す」.2019

    • Author(s)
      漆谷 真
    • Journal Title

      BRAIN and NERVE

      Volume: 7 Pages: 13-23

    • Related Report
      2019 Annual Research Report
  • [Presentation] ALS治療の今と未来展望2021

    • Author(s)
      漆谷 真
    • Organizer
      第62回 日本神経学会学術大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] A single intrathecal injection of OPC expressing scFv against misfolded SOD1 improved ALS model rats2021

    • Author(s)
      南山素三雄、酒井まどか、山口裕子、引網亮太、和田英貴、端真季子、小代明美、牧野晶子、眞木崇州、朝長啓造、高橋良輔、漆谷 真
    • Organizer
      第62回 日本神経学会学術大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] ALSの病原蛋白質に対する抗体治療戦略2020

    • Author(s)
      漆谷 真
    • Organizer
      第61回日本神経学会学術集会.
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Therapeutic effects of bone marrow-derived neuroprotective microglia in ALS model mice2020

    • Author(s)
      小橋修平、寺島智也、柏木駿也、樫 美和子、中江由希、小嶋秀人、漆谷 真
    • Organizer
      第61回 日本神経学会学術大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] novel cell transplantation therapy for familial ALS using oligodendrocyte precursor cells expressing scFv recognizing misfolded SOD12019

    • Author(s)
      Minamiyama S, Sakai M, Yamaguchi Y, Hikiami R, Tamaki Y, Shodai A, Maki T, Tomonaga K, Takahashi R, Urushitani M
    • Organizer
      第60回日本神経学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] novel cell transplantation therapy for familial ALS using oligodendrocyte precursor cells expressing scFv specific for misfolded SOD12019

    • Author(s)
      Minamiyama S, Sakai M, Yamaguchi Y, Hikiami R, Tamaki Y, Shodai A, Makino A, Maki T, Tomonaga K, Takahashi R, Urushitani M
    • Organizer
      30th International Symposium on ALS/MND
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Sequestration of RNA helicase DHX30 from mitochondrion is linked to mitochondrial dysfunction in ALS-FUS2019

    • Author(s)
      Hikiami R, Minamiyama S, Asada M, Wada H, Shodai A, Morimura S, Ayaki T, Takahashi R, Urushitani M
    • Organizer
      30th International Symposium on ALS/MND
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Combined bone marrow transplantation therapy of MNCs and growth factor expressing-MSCs for ALS2019

    • Author(s)
      Terashima T, Kobashi S, Watanabe Y, Nakanishi M, Honda N, Katagi M, Nakae Y, Ohashi N, Urushitani M, Kojima H
    • Organizer
      30th International Symposium on ALS/MND
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Elimination of TDP-43 inclusions linked to amyotrophic lateral sclerosis by a misfolding-specific intrabody.2019

    • Author(s)
      Makoto Urushitani
    • Organizer
      The 42nd Annual Meeting of the Japan Neuroscience Society The 62nd Annual Meeting of the Japanese Society for Neurochemistry
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 筋萎縮性側索硬化症に対する免疫療法2019

    • Author(s)
      漆谷 真
    • Organizer
      第31回日本神経免疫学会学術集会シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ALS病原蛋白質の局在に基づく抗体医療戦略2019

    • Author(s)
      漆谷 真
    • Organizer
      第 37 回日本神経治療学会学術集会シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ALS治療の近未来展望2019

    • Author(s)
      漆谷 真
    • Organizer
      第46回日本脳科学会 基調講演
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ALS免疫療法の新展開2019

    • Author(s)
      漆谷 真
    • Organizer
      第60回日本神経学会学術大会 教育講演
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Book] 神経免疫 メカニズムと疾患2021

    • Author(s)
      漆谷 真
    • Total Pages
      201
    • Publisher
      羊土社
    • ISBN
      9784758103978
    • Related Report
      2021 Annual Research Report
  • [Book] 今日の診断指針 デスク判 第8版2020

    • Author(s)
      永井 良三
    • Total Pages
      2
    • Publisher
      医学書院
    • ISBN
      9784260038089
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
  • [Book] 今日の治療指針 2020年版[デスク判]2020

    • Author(s)
      福井 次矢
    • Total Pages
      2
    • Publisher
      医学書院
    • ISBN
      4260039393
    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 筋萎縮性側索硬化症の原因となる変異型SOD1タンパク質に結合性を有する抗体及び抗体断片2021

    • Inventor(s)
      漆谷 真、守村敏史、南山素三雄
    • Industrial Property Rights Holder
      漆谷 真、守村敏史、南山素三雄
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-143179
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] ボルナウイルスベクターを利用した医薬組成物2021

    • Inventor(s)
      朝長敬造、漆谷 真、南山素三雄
    • Industrial Property Rights Holder
      朝長敬造、漆谷 真、南山素三雄
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-143184
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 異常TDP-43を分解除去する抗体断片2019

    • Inventor(s)
      漆谷真、玉木良高
    • Industrial Property Rights Holder
      漆谷真、玉木良高
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2019 Annual Research Report
    • Overseas

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Published: 2019-04-18   Modified: 2023-01-30  

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