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Development of novel therapy and elucidation of pathophysiology for genetic leukodystrophy

Research Project

Project/Area Number 14370252
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionJikei University School of Medicine

Principal Investigator

ETO Yoshikatsu  Jikei University School of Medicine, Professor, 医学部, 教授 (50056909)

Co-Investigator(Kenkyū-buntansha) OHASHI Toya  Jikei University School of Medicine, Assistant Professor, 医学部, 助教授 (60160595)
IDA Hiroyuki  Jikei University School of Medicine, Assistant Professor, 医学部, 助教授 (90167255)
TSUDA Takashi  Jikei University School of Medicine, Assistant Lecture, 医学部, 講師 (50188554)
MIYATA Ichiro  Jikei University School of Medicine, Assistant Lecture, 医学部, 講師 (10200180)
SUZUKI Hideaki  Jikei University School of Medicine, Assistant, 医学部, 助手 (20206519)
伊藤 建 (伊東 建)  東京慈恵会医科大学, 医学部, 助手 (50276995)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 2004: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2003: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2002: ¥5,800,000 (Direct Cost: ¥5,800,000)
KeywordsGene Therapy / Leucodystrophy / Pre-natal Gene therapy / Krabbe disease / Retrovirus vector / 遺伝性白質変性症 / ムコ多糖症 / Krabbe病 / Twitcherマウス / アデノウイルスベクター / 動物モデル
Research Abstract

We are developing gene and cell therapy for genetic leukodystrophies. The main disease, which we focused on, was Krabbe disease. This disease is caused by a genetic deficiency of galactocerebrosidase and the authentic murine model of Krabbe disease is available. Using this murine model, we tried several gene therapy approaches. First, we injected adenoviral vector, which carries bacterial LacZ gene into lateral ventricles of normal mouse embryo. LacZ expression was observed throughout the brain and this expression was persisted more than 100 days after birth. Main cell type, which expressed LacZ gene was neuron and astorocytes. However, no oligodendrocytes expressed LacZ. Although this approach was very effective for mucopolysaccharidosis type VII mice, mouse model of Krabbe disease failed to be cured by this method. This failure may be due that the main affected cell in Krabbe disease is oligodendrocyte. So we tested retroviral vector instead of adenovirus vector. As a result, not only neurons and astrocytes, but also olingodendrocytes expressed LacZ, and the expression period was more than 100 days without significant decrement of expression. This observation strongly indicated that retrovirus vector transdused neural stem cell. So we injected retorovirus vector into subventricular zone of newborn mouse brain, which is known that many neural stem cells exist. In this case, mainly, astorcyte and oligidendrocyte expressed LacZ. From this observation, we generated retrovirus vector which expressed galactocerebrosidase and injected subventricular zone of newborn twitcher mouse, which is authentic mouse model of Krabbe disease. The abnormal morphology of twitcher mouse oligodedrocyte was restored by retrovirus transduction. This indicated that neonatal gene therapy may be feasible for treatment of neural involvement of Krabbe disease.

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (23 results)

All 2005 2004 2003 Other

All Journal Article (12 results) Book (1 results) Publications (10 results)

  • [Journal Article] Widespread and highly persistent gene transfer to the CNS by retrovirus vector in utero : Implication for gene therapy to Krabbe disease.2005

    • Author(s)
      Shen JS, Meng XL, Yokoo T, Sakurai K, Watabe K, Ohashi T, Eto Y.
    • Journal Title

      J Gene Med (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] GALC transduction leads to morphological improvement of the twitcher oligodendrocytes in vivo.2005

    • Author(s)
      Meng XL, Shen JS, Watabe K, Ohashi T, Eto Y.
    • Journal Title

      Mol Genet Metab. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Widespread and highly persistent gene transfer to the CNS by retrovirus vector in utero : Implication for gene therapy to Krabbe disease.2005

    • Author(s)
      Shen JS, Meng XL, Yokoo T, Sakurai K, Watabe K, Ohashi T, Eto Y.
    • Journal Title

      J Gene Med. (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 先天性代謝異常症 疾患モデル動物2004

    • Author(s)
      衛藤義勝
    • Journal Title

      別冊医学のあゆみ

      Pages: 73-75

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Treatment of lysosomal storage disorders : Cell therapy and gene therapy.2004

    • Author(s)
      Eto Y, Shen JS, Meng XL, Ohashi T.
    • Journal Title

      J Inherit Metab Dis. 27(3)

      Pages: 411-415

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Brain transplantation of genetically modified bone marrow stromal cells corrcts CNS pathology and cognitive function in MPS VII mice.2004

    • Author(s)
      Sakurai K, Iizuka S, Shen JS, Meng XL, ori_T, _Umezawa A, Ohashi T, Eto Y
    • Journal Title

      Gene Ther 11(19)

      Pages: 1475-1481

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Widespread gene transduction to the central nervous system by adenovirus in utero : Implication for prenatal gene therapy to brain involvement of lysosomal storage disease2004

    • Author(s)
      Shen JS, Meng XL, Maeda H, Ohashi T, Eto Y.
    • Journal Title

      J Gene Med 6(11)

      Pages: 1206-1215

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Widespread gene transduction to the central nervous system by adenovirus in utero : Implication for prenatal gene therapy to brain involvement of lysosomal storage disease.2004

    • Author(s)
      Shen JS, Meng XL, Maeda H, Ohashi T, Eto Y.
    • Journal Title

      J Gene Med. 6(11)

      Pages: 1206-1215

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice.2004

    • Author(s)
      Sakurai K, Iizuka S, Shen JS, Meng XL, Mori T, Umezawa A, Ohashi T, Eto Y.
    • Journal Title

      Gene Ther. 11(19)

      Pages: 1475-1481

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Brain transplantation of genetically modified bone marrow stromal cells corrects CNS pathology and cognitive function in MPS VII mice.2004

    • Author(s)
      Sakurai K, Iizuka S, Shen JS, Meng XL, Mori T, Umezawa A, Ohashi T, Eto Y
    • Journal Title

      Gene Ther 11(19)

      Pages: 1475-1481

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Widespread gene transduction to the central nervous system by adenovirus in utero : Implication for prenatal gene therapy to brain involvement of lysosomal storage disease.2004

    • Author(s)
      Shen JS, Meng XL, Maeda H, Ohashi T, Eto Y.
    • Journal Title

      J Gene Med 6(11)

      Pages: 1206-1215

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Braintransplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse.2003

    • Author(s)
      Meng XL, Shen JS, Ohashi T, Maeda H, Kim SU, Eto Y.
    • Journal Title

      J Neurosci Res. 74(2)

      Pages: 266-277

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] ファブリー病について,ファブリー病2004

    • Author(s)
      衛藤義勝, 井田博幸
    • Total Pages
      7
    • Publisher
      ブレーン出版(株)
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Publications] 衛藤 義勝: "Fabry病 特集 小児の疼痛のコントロール"小児内科. 35・8. 1380-1383 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 衛藤 義勝, 大橋 十也, 他: "日本人ファブリー病患者における酵素補充療法:第II相オープン試験の結果"小児科診療. 66・8. 1435-1444 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 衛藤 義勝, 大橋 十也, 他: "ファブリー病患者に対するα-ガラクトシダーゼA補充療法の他施設臨床試験成績"小児科臨床. 56. 133-143 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 衛藤 義勝: "酵素補充療法の最近の進歩 特集 小児薬物療法に関する最近の話題"小児科. 44・9. 1342-1352 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 衛藤 義勝: "Fabry病 小児疾患診療の為の病態生理"小児内科. 35. 461-467 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Meng XL, Shen JS, Ohashi T, Maeda H, Kim SU, Eto Y: "aintransplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse"J Neurosci Res. 74(2). 266-277 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Eto Y, Ohashi T: "Novel treatment for neuronopathic lysosomal storage diseases-cell therapy/gene therapy"Current Molecular Medicine. 2(1). 83-89 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uehara R, Eto Y, et al.: "Novel nonsense mutation of the BMPR-II gene in a Japanese patient with familial primary pulmonary hypertension"Pediatrics International. 44(4). 433-435 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Akiyama M, Eto Y, et al.: "Telomerase overexpression in K562 leukemia cells protects against apoptosis by serum deprivation and double-stranded DNA break inducing agents, but not against DNA synthesis inhibitors"Cancer Letters. 178(2). 187-197 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shen JS, Eto Y, et al.: "Adenovirus-mediated prenatal gene transfer to murine central nervous system"Gene Therapy. 9(12). 819-823 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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