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Gene therapy for chronic granulomatous disease combined with in vivo expansion of transduced hematopoietic cells.

Research Project

Project/Area Number 14570768
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionJichi Medical School

Principal Investigator

KUME Akihiro  Jichi Medical School, Faculty of Medicine, Associate Professor, 医学部, 助教授 (10264293)

Co-Investigator(Kenkyū-buntansha) OZAWA Keiya  Jichi Medical School, Faculty of Medicine, Professor, 医学部, 教授 (30137707)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsgene therapy / chronic granulomatous disease / translational research / hematopoietic stem cells / selecvtive amplifier gene / retroviral vector / innate immunity / phagocytes / 活性酸素 / 移植・再生医療
Research Abstract

We have developed 'selective amplifier genes (SAGs)' which encode chimeric receptors to confer in vivo growth advantage on transduced hematopoietic cells. In this project, we investigated the feasibility of using SAGs to boost clinical benefit of gene therapy in a mouse model of X-linked chronic granulomatous disease (X-CGD). (1)A fusion receptor GcRER was constructed with the granulocyte colony-stimulating factor receptor and the estrogen-binding domain. X-CGD bone marrow cells were transduced by a retroviral vector encoding GcRER and gp91-phox, the latter of which is deficient in X-CGD. The transduced cells were reinfused into irradiated X-CGD mice for hematopoietic reconstitution. After recovery, estrogen was administered to a subset of the transplants, and the estrogen-treated animals had a significantly higher level of functionally corrected granulocytes. (2)As a second generation of SAGs, the extracellular domain of erythropoietin receptor (EpoR) was employed as a molecular switch to regulate cell growth signaling. EpoR was fused to the cytoplasmic domain of c-Mpl, and the gene for the chimera (EpoRMpl) was inserted into a retroviral vector together with the gp91-phox gene. X-CGD bone marrow cells were transduced with the vector and transplanted to X-CGD recipients as in the previous experiments. Erythropoietin administration to the recipient animals resulted in an elevation of functionally corrected granulocytes.
These results indicated that SAG-mediated expansion of transduced hematopoietic cells is feasible in gene therapy for X-CGD.

Report

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

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Kume A, et al.: "In vivo expansion of transduced murine hematopoietic cells with a selective amplifier gene."The Journal of Gene Medicine. 5. 175-181 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagashima T, et al.: "New selective amplifier genes containing c-mpl for hematopoietic cell expansion."Biochemical and Biophysical Research Communications. 303. 170-176 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Itoh A, et al.: "A soluble CAR-SCF fusion protein improves adenoviral vector-mediated gene transferto c-Kit positive hematopoietic cells."The Journal of Gene Medicine. 5. 929-940 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagashima T, et al.: "In vivo expansion of gene-modified hematopoietic cells by a novel selective amplifier gene utilizing the erythropoietin receptor as a molecular switch."The Journal of Gene Medicine. 6. 288-299 (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hara T, et al.: "Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene."Gene Therapy. in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mochizuki S, et al.: "Long-term correction of hiperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice."Gene Therapy. in press.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kume A et al.: "In vivo expansion of transduced murine hematopoietic cells with a selective amplifier gene."J Gene Med. 5(3). 175-181 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagashima T et al.: "New selective amplifier genes containing c-mpl for hematopoietic cell expansion."Biochem Biophys Res Commun. 303(1). 170-176 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Itoh A et al.: "A soluble CAR-SCF fusion protein improves adenoviral vector-mediated gene transferto c-Kit-positive hematopoietic cells."J Gene Med. 5(11). 929-940 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagashima T et al.: "In vivo expansion of gene-modified hematopoietic cells by a novel selective amplifier gene utilizing the erythropoietin receptor as a molecular switch."J Gene Med. 6(1). 22-31 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hara T et al.: "Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring herapeutic gene and a selective amplifier gene."Gene Ther. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mochizuki S et al.: "Long-term correction of hiperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice."Gene Ther. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Kametaka M, et al.: "Reduction of CTLL-2 cytotoxicity by inducible apoptosis with a Fas-estrogen receptor chimera"Cancer Science. 94(7). 153-157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Itoh A, et al.: "A soluble CAR-SCF fusion protein improves adenoviral vector-mediated gene transfer to c-Kit-positive hematopoietic cells"The Journal of Gene Medicine. 5(11). 929-940 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Xu R, et al.: "G-CSF receptor-mediated STAT3 activation and granulocyte differentiation in 32D cells"Gene Therapy and Molecular Biology. 7. 167-172 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagashima T, et al.: "In vivo expansion of gene-modified hematopoietic cells by a novel selective amplifier gene utilizing the erythropoietin receptor as a molecular switch"The Journal of Gene Medicine. 6(1). 22-31 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hara T, et al.: "Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene"Gene Therapy. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mochizuki S, et al.: "Long-term correction of hiperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice"Gene Therapy. in press. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hanazono Y et al.: "In vivo selective expansion of gene-modified hematopoietic cells in a nonhuman primate model"Ggne Therapy. 9(16). 1055-1064 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kume A et al.: "Selective growth advantage of wild-type lymphocytes in X-linked SCID recipients"Bone Marrow Transplantation. 30(2). 113-118 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Asano T et al.: "Highly efficient gene transfer into primate embryonic stem cells with a simian lentivirus vector"Molecular Therapy. 6(2). 162-168 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kume A et al.: "Selective expansion of transduced cells for hematopoietic stem cell gene therapy"International Journal of Hematology. 76(4). 299-304 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kume A et al.: "In vivo expansion of transduced murine hematopoietic cells with a selective amplifier gene"The Journal of Gene Medicine. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagashima T et al.: "New selective amplifier genes containing c-mpl for hematopoietic cell expansion"Biochemical and Biophysical Research Communications. (in press).

    • Related Report
      2002 Annual Research Report

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

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