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Molecular Pathogenesis of Brain Damage and Gene Therapy in Genetic Leukodystrophy

Research Project

Project/Area Number 11470176
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionThe Jikei University Shool of Medicine

Principal Investigator

ETO Yoshikatsu  Jikei Univ.,Dept. of Pedatrics Prof., 医学部, 教授 (50056909)

Co-Investigator(Kenkyū-buntansha) TSUDA T  Jikei Univ.,Dept. of Pedatrics, senior investigator, 医学部, 助手 (50188554)
OHASHI Toya  Jikei Univ.,Dept. of Pedatrics, asso prof., 医学部, 助教授 (60160595)
IDA Hiroyuki  Jikei Univ.,Dept. of Pedatrics, assi prof., 医学部, 講師 (90167255)
KUROSAWA Kenji  Jikei Univ.,Dept. of Pedatrics, senior investigator, 医学部, 助手 (20277031)
HASEGAWA Yoriyasu  Jikei Univ.,Dept. of Pedatrics, senior investigator, 医学部, 助手 (60256435)
Project Period (FY) 1999 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2001: ¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 1999: ¥6,500,000 (Direct Cost: ¥6,500,000)
KeywordsMLD / gene therapy / neural stem cell therapy / Twitcher mice / Sly mice / 遺伝子異常 / Sjogren-Larsson
Research Abstract

1. Pathogenesis of Leukodystrophy in Globoide Cell Leukodystrophy and Other
1) Using animal model of Krabbe globoid cell leukodystrophy(GLD), we tried to identified the cause of leukodytrophy in twitcher mice. The cause of neural cell damage might be caused by the influx of intracellular calcium in such mice which was demonstrated by patch cramp method. The increased intracellular calcium resulted in the activation of cellular protease and hense damage the neural cells.
2) We studied the clinical phnotype and genotype in metachromatic leukodystrophy and also identified novel genotype in two cases with MLD. Furthermore, we demonstrated that the G99D mutation was neruological severe type and consisted of 50% of all genotype of Japanese MLD.
3) Japanese patients with Sjogren Larrson syndrome shows particular genotype in Japanese.
4) We studied the genotype identifications in Fabry disease which were L16H, A37V, W209X, 342QIVS-1-1 etc.
2. Cell therapy and gene therapy in genetic leukodystrophy
Gene therapy and cell therapy were carried out using Twitcher mice and Sly Mice.
1) Twitcher mice were treated with adenovirus vector which was administered into intraventricle, during fetal period. The number of globoid cells were decreased in treated animals after the administration of viral vetor. Simultaneously, the amount of psychosine was decreased in treated animals.
2) Neural stem cells obtained fromhuman fetal brains were injected into Sly mice brain and the accumulated compounds in Sly mice were decreased. The data suggest that neural stem cells were effective for the treatment of The CNS involvement in these neurological mutants.
3) Injection of mesenchymal stem cells into Sly mice showed decreased storage Materials and effective for neurological mice.

Report

(4 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Ida H, Eto Y, et al.: "Effects of enzyme replacement therapy in 13 Japanese pediatric patients with Gaucher disease"Eur J Pediatr. 160. 21-25 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoo T, Ohashi T, Eto Y, et al.: "Inflamed glomeruli-specific gene activation that uses recombinant adenovirus with the Cre/loxP system"J Am Soc Nephrol. 12(11). 2330-2337 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoo T, Ohashi T, Eto Y, et al.: "Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses"Blood. 98(1). 57-64 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Watabe K, Ida H, Eto Y, et al.: "Establishment and characterization of immortalized Schwann cells from murine model of Nieman-Pick disease・・・"J Peripheral Nervous System. 6. 85-94 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsuda M, Ida H, Eto, et al.: "A newly recognized missennse mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome"Eur J Pediatr. 160. 867 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kimura T, Ohashi T, Eto Y, et al.: "The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial・・・"Cancer. 92. 2555-2561 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ida H, Rennert OM, Kobayashi M and Eto Y: "Effects of enzyme replacement therapy in 13 Japanese pediatric patients with Gaucher disease."Eur J Pediatr.. 160. 21-25 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoo T, Ohashi T, Utsunomiya Y, Shiba H, Shen JS, Hisada Y, Eto Y, Kawamura T, Hosoya T: "Inflamed glomeruli-specific gene activation that uses recombinant adenovirus with the Cre/loxP system."J Am Soc Nephrol.. 12(11). 2330-2337 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yokoo T, Ohashi T, Utsunomiya Y, Shen JS, Hisada Y, Eto Y, Kawamura T, Hosoya T: "Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome."Blood. 98(1). 57-64 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Watabe K, Ida H, Tanaka J, Miyawaki S, Ohno K and Eto Y: "Establishment and characterization of immortalized Schwann cells from murine model of Nieman-Pick disease C(spm/spm)"J Perlpjeral Nervous System. 6. 85-94 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsuda M, Kitasawa E, Ida H, Eto Y and Owada M: "A newly recognized missennse mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome."Eur J Pediatr. 160. 867 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kimura T, Suzuki H, Ohashi T, Asano Kouji, Kiyota H, Eto Y: "The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinornas."Cancer. 92. 2555-2561 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shen J. Watabe K, Ohashi T, Eto Y: "intraventricular administration of recombinant adenovirus to neonatal twitcher muse leads to clinicopathological improvements."Gene Ther. 8(14). 1081-1087 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, Taira N, Eto Y: "Frontal lobe dementia with abnormal cholesterol metaboilsm and heterozygous mutation in sterol 27-hydroxylase gene(CYP27)"J Inherit Metab Dis. 24(3). 379-392 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Shiba H, Okamoto T, Futagawa Y, Ohashi T, Eto Y: "Efficient and cancer-selective gene transfer to hepatocellular carcinoma in a rat using adenovirus vector with iodized oil esters."Cancer Gene Ther. 8(10). 713-718 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Watabe K, Sakamoto T, Ohashi T, Kawazoe Y, Oyanagi K, Takeshima T, Inoue K, Eto Y, Kim SU: "Adenoviral gene transfer of glial cell line-derived neurotrophic factor to injured adult motoneurons."Hum Cell. 14(1). 7-15 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Eto Y, Ohashi T: "Gene therapy/cell therapy for lysosomal strange disease."J Inhert Metab Dis. 23(3). 293-298 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ohashi T., Yokoo T., Iizuka S., Kobayashi H., Sly W.S. and Eto Y: "Reduction of lysosomal storage in Murine Mucoplysaccharidosis Type VII by Transplantation of Normal and Genetically Modified Macrophages."Blood. 95(11). 3631-3633 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Watabe K., Ohashi T., Sakamoto T., Kawazoe y., Takeshima T., Oyanagi K., Inoue K., Eto Y., and Kim S.U.: "Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor."Journal of Neuroscience Research. 60. 511-519 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tsujino S., Kanazawa N., Ohashi T., Eto Y., Saito T., Kira J. Yamada T: "Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with HHH syndrome."Arch of Neurol. 147(5). 625-631 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamada T: "Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with HHH syndrome."Arch of Neurol. 147(5). 625-631 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miyata I, Toyoda S and Eto Y: "Selective hypoaldosteronism with hypothyroidism in infancy"Clinical Endoerinology. 9(2). 55-62 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ida H, Eto Y, et al: "Effects of enzyme replacement therapy in 13 Japanese pediatric patients with Gaucher disease"Eur J Pediatr. 160. 21-5 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yokoo T, Ohashi T, Eto Y, et al: "Inflamed glomeruli-specific gene activation that uses recombinant adenovirus with the Cre/loxP system…"J Am Soc Nephrol. 12(11). 2330-7 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yokoo T, Ohashi T, Eto Y, et al: "Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury…"Blood. 98(1). 57-64 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Watabe K, Ida H, Eto Y, et al: "Establishment and characterization of immortalized Schwann cells from murine model of Nieman-Pick disease C(spm/spm)"J Peripheral Nervous System. 6. 85-94 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuda M, Ida H, Eto, et al: "A newly recognized missennse mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome"Eur J Pediatr. 160. 867 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kimura T, Ohashi T, Eto Y, et al: "The incidence of thanatophoric dysplasia mutations in FGFR3 gene is higher in low-grade or superficial bladder carcinomas"Cancer. 92. 2555-2561 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Eto Y.,Ohashi T.: "Gene therapy/cell therapy for lysosomal storage disease."J Inherited Metabo Dis. 23(3). 293-8 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Futagawa Y.,Okamoto T.,Ohashi T.,Eto Y.: "Efficiency of adenovirus-mediated gene Transfer into hepatocytes by liver asanguineous perfusion method."Res Exp Med (Berl). 199(5). 263-74 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsukuno M.,Suzuki H.,Eto Y.: "Reply to the critique : Pfeiffer syndrome is most likely caused by haploinsufficient mutation of FGFR2 in our cases."J Craniofac Genet Dev Biol. 20. 112 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyata I,Inagami T and Eto Y.: "Physiotogical Function and Localization of a Short Isoform of the Corticotropin-Releasing Factor Receptor Subtype (CRF2α-tr) in the Rat Brain."Endocrinology. 9(2). 55-62 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ohashi T.,Yokoo T.,Eto Y.: "Eduction of Lysosomal storage in Murine Mucoplysaccharidosis Type VII by Transplantation of Normal and Genetically Modified Macrophages."Blood. 95(11). 3631-3 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ida H,Rennert OM,Kobayashi M and Eto Y.: "Effects of enzyme replacement therapy in 13 Japanese pediatric patients with Gaucher disease."Eur J Pediatr. (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Eto Y., Ida H.: "Clinical and molecular Characteristics of Japanese Gaucher Disease."Neurochem Res. 10. 2673-2678 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ohashi T., Yokoo T., Eto Y., et al.: "Eduction of Lysosomal storage in Murine Mucoplysaccharidosis・・・"Blood. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watabe K., Ohashi T., Eto Y., et al.: "Rescue of lesioned adult rat spinal motoneurons by・・・"Journal of Neuroscience Research. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Ida H., Rennert OM., Eto Y., et al.: "Clinical and genetic studies of Japanese homozygotes for the・・・"Hum Genet. 105. 120-126 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Oishi K., Ida H., Eto Y., et al.: "Clinical and molecular of Japanese patients with neuronal・・・"Molecular Genetics and Metabolism. 66. 344-348 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yokoo T., Ohashi T., Eto Y., et al.: "Prophyaxis of Antibody-Induced Acute Glomerulonephritis・・・"Hum Gene Ther. 10. 2673-2678 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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