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Studies for Gene Therapy of Sphingolipidosis

Research Project

Project/Area Number 10044321
Research Category

Grant-in-Aid for Scientific Research (B).

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

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) GIESELMANN V  Univ. of Kiel, Prof., 教授
BARRANGER J.a.  Univ. of Pittsburgh, Dept. of Human Genetics, Pediatr., Prof., 教授
BRADY R.d.  NHI, Developmental and Metabolic Neurology Branch, Chief, 部長
BARRANGER J. A.  ピッツバーグ大学, 医学部, 教授
GIESELMANN V  キール大学, 医学部, 教授
BARRANGER J.  ピッツバーグ大学, 医学部, 教授
BRADY R.O.  NIH Developmental and Metabolic Neurolig, 部長
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1999: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1998: ¥3,100,000 (Direct Cost: ¥3,100,000)
Keywordslipidosis / Gene analysis / Gene therapy / neuronal cells / 造血幹細胞 / アデノウイルスベクター / 先天代謝異常症 / 遺伝子治療 / 中枢神経症状 / 動物モデル
Research Abstract

Gene analysis of Japanese lipidodes patients :
We analyzed gene from various Japanese patients with lipidoses and found that the distribution of gene mutations was quite different from that from other ethnic groups.
Gene therapy :
The deficiency of human β-glucuronidase(HBG) results in MPS type VII(Sly syndrome). In this study, we tested the ability to target CD18/CD11b positive cells with gene therapy for murine MPS VII. We harvested bone marrow cells from syngeneic normal mice and cultivated in CSF-1 containing medium for 2 weeks. More than 95% of the cells were double positive for CD18/CD11b by flowcytometry. We gave 2×10ィイD16ィエD1 cells to the non-myeloablated Sly mouse. One week post-transplantation, donor cells populated liver and spleen. The HBG activity increased from 0.9±0.7 to 28.4±12.5u/mg and 0.7±0.4 to 29.7±23.1u/mg in liver and spleen respectively. However, the pathology was unchanged. The HBG activity in liver and spleen decreased b 5 weeks to 3.7±1.5 and 2.3±0.5 respectivel … More y, but the pathological improvements were significant and glycosaminoglycan storage was largely cleared. Next, the CD18/CD11b cells were collected from Sly mouse by the method above, transduced by HBG expressing retrovirus(MFG-HBG), and given to non-myeloablated Sly mouse. By 5 weeks post-transplantation, HBG activity was only marginally above the control level. However, many HBG positive cells were observed and pathological improvement was significant. These data suggest that CD18/CD11b cells transplantation is promising for treatment of murine MPS VII without myeloablation, and CD18/CD11b cells may be a good targets for gene therapy for Sly syndrome.
Gene transfer to neuronal cells :
Because significant prenatal pathology occurs in genetic diseases, postnatal therapy is often not sufficient to correct them, especially if damage has occurred in the central nervous system. In such diseases, prenatal treatment will be required. Adenovirus mediated gene transfer may be useful for this purpose because of its wide host range and efficient gene transfer to various organs. However, most of the gene transfer studies have been carried out at a relatively late stage of embryogenesis. In this study, a recombinant adenovirus expressing the E. coli lacZ gene (AxCALacZ) was administered into the rat embryos at the 8th to 12th day of gestation. The results of the study revealed that the lacZ gene was expressed in many different organs including liver, heart, skin and brain. These results suggest that the adenovirus vector may be useful for the prenatal gene therapy of many genetic diseases. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Eto Y., Ida H.: "Clinical and molecular Characteristics of Japanese Gaucher Disease."Neurochem Res. 24(2). 207-11 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohashi T., Yokoo T., Eto Y., et al: "Eduction of Lysosomal storage in Murine Mucoplysaccharidosis・・・"Blood. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Watanabe K., Ohashi T., Eto Y., et al: "Rescue of lesioned adult rat spinal motoneurons by・・・"Journal of Neuroscience Research. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ida H., Rennert OM., Eto Y., et al.: "Clinical and genetic studies of Japanese homozygotes for the・・・"Hum Genet. 105. 120-6 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Oishi K., Ida H., Eto Y., et al: "Clinical and molecular of Japanese patients with neuronal・・・"Molecular Genetics and Metabolism. 66. 344-8 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yokoo T., Ohashi T., Eto Y., et al.: "Prophyaxis of Antibody-Induced Actue Glomerulonephritis・・・"Hum Gene Ther. 10. 2673-8 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohashi,T., Yokoo,T., Lizuka,S., Kobayashi,H., Sly,W.S., Eto,Y.: "Education of Lysosomal storage in Murine Mucoplysaccharidosis Type VII by Transplantation of Normal and Genetically Modified Macrophages."Blood. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Watabe,K., Ohashi,T., Sakamoto,T., Eto,Y., et al.: "Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor."Journal of Neuroscience Research. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsujino,S., Kanazawa,N., Ohashi,T., Eto,Y., et al.: "Three novel mutations (G27E, insAAC, R179X) in the ORNT1 gene of Japanese patients with HHH syndrome."Arch of Neurol. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsukuno,M., Suzuki,H., Eto,Y., Miyata,I., Toyoda,S., Eto,Y.: "Selective hypoaldosteronism with hypothyroidism in infancy."Clinical Endocrindology. in press. (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Tsukuno,M., Szuki,H., Eto,Y., Miyata,I., Toyoda,S., Eto,Y.: "Pfeiffer syndrome caused by haploinsufficiency mutation of FGFR2."J Craniofac Genet Dev Biol. 19. 183-188 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Eto,Y., Ida,H.: "Clinical and molecular characteristics of Japanese Gaucher Disease."Neurochem Res. 24(2). 207-211 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Yokoo,T., Ohashi,T., Utsunomiya,Y., Eto,Y., et el: "Prophyaxis of Antibody-Induced Acute Glomerulonephritis with Genetically Modified Bone Marrow-Derived Vehichle Cells."Hum Gene Ther. 10. 2673-2678 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ida,H., Rennert,OM., Iwasawa,K., Kobayashi,M., Eto,Y.: "Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutations."Hum Genet. 105. 120-126 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ida,H., Rennert,OM., Eto,Y., et al.: "Severe skeletal complications in Japanese patients with type 1 Gaucher disease."J Inher Metab Dis. 22. 63-73 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Oishi,K., Kurosawa,K., Ida,H., Eto,Y.: "Clinical and molecular of Japanese patients with neuronal ceroid lipofuscinosis."Molecular Genetics and Metabolism. 66. 344-348 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ohashi,T., Lizuka,S., Sly,W.S., Machiki,Y., Eto,Y.: "Efficient and persistent expression of β-glucuronidase gene in CD34+cells from human umbiical cord blood by retroviral vector."Eur J Haematol. 61(4). 235-239 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kurosawa,K., Ida,H., Eto,Y.: "Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy ; identification of two novel mutations."J.Inher Metab Dis. 21. 781-782 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ida,H., Rennert,OM., Ito,T., Maekawa,K., Eto,Y.: "Type 1 Gaucher Disease : Phenotypic Expression and Natual History in Japanese Patients."Blood Cells, Molecules, and Disease. 24(5). 73-81 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Eto Y., Ida H.: "Clinical and molecular Characteristics of Japanese Gaucher Disease"Neurochem Res. 24(2). 207-211 (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). (2000)

    • 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
  • [Publications] Ida H,Eto Y.,et al.: "Severa skeketal complications in Japanese patients with type 1 Gaucher disease." J Inher Matab Dis. 22. 63-73 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ohashi T,Eto Y.,et al.: "Efficient and persistent expression of β-glucuronidase gene in CD34+cells from human umbilical cord blood by retroviral vector." Eur J Haematol. 61. 235-239 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yokoo T,Eto Y.,et al.: "Inflamed site-specific gene delivery using bone marrow-derived CD11b+CD18+Vehicle cells mice." Hum.Gene Ther. 9. 17381-17388 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ida H,Eto Y.,et al.: "Type 1 Gaucher Disease:Phenotypic Expression and Natural History in Japanese Patients." Blood Cells,Molecules,and Disease. 24・5. 73-81 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kurosawa K.,Eto Y.,et al.: "Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy:Identification of two novel mutations." J.Inher.Metab.Dis.21. 781-782 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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