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Development of gene therapy system for refractory leukemia using RNA interference technology

Research Project

Project/Area Number 16590927
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionThe University of Tokyo

Principal Investigator

SODA Yasushi  The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (00361618)

Co-Investigator(Kenkyū-buntansha) TOJO Arinobu  The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (00211681)
KAWASAKI Hiroaki  The University of Tokyo, Graduate School of Engineering, Research Associate, 大学院・工学系研究科, 助手 (60332623)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsPhiladelphia chromosome / acute lymphoblastic leukemia (ALL) / gene therapy / bcr-abl / RNAi / HIV vector / 急性リンパ性白血病 / shRNA
Research Abstract

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph^+ ALL) is one of the most refractory leukemia, and prognosis of patients with this disease is very poor. To develop a new gene therapy system against this disease, we examined effect of short hairpin RNAs (shRNA) targeting P190-type bcr-abl gene on survival and growth of Ph^+ ALL cells. We designed a number of 21- and 27-mer shRNAs targeting fusion site of the bcr-abl gene, 21-mer shRNAs targeting c-abl gene. After screening of these shRNAs, we could obtain some shRNAs that decrease P190^<BCR-ABL> efficiently. We produced HIV(VSV) vectors encoding these shRNAs under control of U6 promoter, and examined the effect of these shRNA on some leukemia cell lines. The 21-mer shRNA vector targeting bcr-abl induced Ph^+ ALL cell death specifically, but this effect was only transient, and the 27-mer shRNA vector scarcely induced cell death. In contrast, the 21-mer shRNA vector targeting c-abl efficiently killed both Ph^+ ALL and chronic-myeloid leukemia cells, which express P210-type bcr-abl. To determine the effect of the shRNA vectors on mutant P190^<BCR-ABL> harboring cells, which are resistant to imatinib, we transduced Ba/F3 cells harboring wild type or mutant P190-type bcr-abl gene with the shRNA vectors. The 21-mer shRNAs targeting bcr-abl and c-abl induced cell death of Ba/F3 cells transduced with wild type bcr-abl or mutant bcr-abl gene almost completely. In contrast, the 27-mer shRNA induced only week cytocidal effect. The effect of 21-mer shRNAs was considered to be dependent on the degree of P190^<BCR-ABL> inhibition, but the reason of week effect of the 27-mer shRNA remained to be resolved. Although the effect of these shRNAs on leukemia cells from Ph^+ ALL patients and normal hematopoietic cells should be further determined, our data suggested that shRNA targeting pathogenic bcr-abl gene may be a useful tool for the Ph^+ ALL gene therapy.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (31 results)

All 2006 2005 2004 Other

All Journal Article (31 results)

  • [Journal Article] Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase2006

    • Author(s)
      Nagano K, Itagaki C, Soda Y, et al.
    • Journal Title

      Oncogene 25・4

      Pages: 493-502

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antiangiogenic activity of BAI1 in vivo : implications for gene therapy of human glioblastomas2006

    • Author(s)
      Kang X, Xiao X, Soda Y, et al.
    • Journal Title

      Cancer Gene Therapy 13・4

      Pages: 385-392

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals2006

    • Author(s)
      Inoue Y, Tojo A, Soda Y, et al.
    • Journal Title

      European Journal of Nuclear Medicine and Molecular Imaging 35・5

      Pages: 557-565

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] p51/p63, a novel p53 homologue, potentiates p53 activity and is a human cancer gene therapy candidate2006

    • Author(s)
      Kunisaki R, Ikawa S, Soda Y, et al.
    • Journal Title

      Journal of Gene Medicine (印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase2006

    • Author(s)
      Nagano K, Itagaki C, Soda Y, et al.
    • Journal Title

      Oncogene 25-4

      Pages: 493-502

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antiangiogenic activity of BAl1 in vivo : implications for gene therapy of human glioblastomas2006

    • Author(s)
      Kang X, Xiao X, Soda Y, et al.
    • Journal Title

      Cancer Gene Therapy 13-4

      Pages: 385-392

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] In vitro validation of bioluminescent monitoring of disease progression and therapeutic response in leukaemia model animals2006

    • Author(s)
      Inoue Y Tojo A, Soda Y, et al.
    • Journal Title

      European Journal of Nuclear Medicine and Molecular Imaging 35-5

      Pages: 557-565

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The synthetic peptide derived from the NH2-terminal extracellular region of an orphan G protein-coupled receptor, GPR1, preferentially inhibits infection of X4 HIV-12005

    • Author(s)
      Jinno-Oue A, Shimizu N, Soda Y, et al.
    • Journal Title

      Journal of Biological Chemistry 280・35

      Pages: 30924-30934

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia2005

    • Author(s)
      Ooi J, Iseki T, Soda Y, et al.
    • Journal Title

      International Journal of Hematology 81・5

      Pages: 424-427

    • NAID

      10016453573

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Atypical hypersensitivity to mosquito bites without natural killer cell proliferative disease in an adult patient2005

    • Author(s)
      Konuma T, Uchimaru K, Soda Y, et al.
    • Journal Title

      International Journal of Hematology 82・5

      Pages: 441-444

    • NAID

      10016917102

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia2005

    • Author(s)
      Ooi J, Iseki T, Soda Y, et al.
    • Journal Title

      International Journal of Hematology 81-5

      Pages: 424-427

    • NAID

      10016453573

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Atypical hypersensitivity to mosquito bites without natural killer cell proliferative disease in an adult patient2005

    • Author(s)
      Konuma T, Uchimaru K, Soda Y. et al.
    • Journal Title

      International Journal of Hematology 82-5

      Pages: 441-444

    • NAID

      10016917102

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The synthetic peptide derived from the NH2-terminal extracellular region of an orphan G protein-coupled receptor, GPR1, preferentially inhibits infection of X4 HIV-12005

    • Author(s)
      Jinno-Oue A, Shimizu N, Soda Y, et al.
    • Journal Title

      Journal of Biological Chemistry 280

      Pages: 30924-30934

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Rb plays a role in survival of Abl-dependent human tumor cells as a downstream effector of Abl tyrosine kinase2005

    • Author(s)
      Nagano K, Itagaki C, Soda Y, et al.
    • Journal Title

      Oncogene 9月12日電子出版

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Antiangiogenic activity of BAI1 in vivo : implications for gene therapy of human glioblastomas2005

    • Author(s)
      Kang X, Xiao X, Soda Y, et al.
    • Journal Title

      Cancer Gene Therapy 10月21日電子出版

    • Related Report
      2005 Annual Research Report
  • [Journal Article] PGK and CMV Promoters Exert the Strongest Activity in Lentiviral Gene Transduction of Myeloid Cells Including Mature Neutrophils2005

    • Author(s)
      Soda Y, Tani K, Li X, et al.
    • Journal Title

      Molecular Therapy 11・S1

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Hematopoietic Cell Differentiation from Common Marmoset (Callithrix jacchus) Embryonic Stem Cells by Their Genetic Manipulation Using the Third Generation Lentiviral Vector2005

    • Author(s)
      Yokoo T, Kurta R, Soda Y, et al.
    • Journal Title

      Molecular Therapy 11・S1

    • Related Report
      2005 Annual Research Report
  • [Journal Article] CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells2004

    • Author(s)
      Harata M, Soda Y, Tojo A, et al.
    • Journal Title

      Blood 104・5

      Pages: 1442-1449

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Unrelated cord blood transplantation after myeloablative conditioning in patients over the age of 45 years2004

    • Author(s)
      Ooi J, Soda Y, Tojo A, et al.
    • Journal Title

      British Journal of Haematology 126・5

      Pages: 711-714

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Hematopoietic activity of common marmoset CD34 cells isolated by a novel monoclonal antibody MA242004

    • Author(s)
      Izawa K, Soda Y, Tojo A, et al.
    • Journal Title

      Experimental Hematology 32・9

      Pages: 843-851

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] Phase I study of autologous tumor vaccines transduced with the GM-CSF gene (GVAX^【○!R】) in four patients with Stage IV renal cell cancer in Japan : clinical and immunological findings2004

    • Author(s)
      Tani K, Soda Y, Asano S, et al.
    • Journal Title

      Molecular Therapy 10・3

      Pages: 799-816

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Anti-NK cell treatment induces stable mixed chimerism in MHC-mismatched, T cell-depleted, nonmyeloablative bone marrow transplantation2004

    • Author(s)
      Cho SG, Soda Y, Tojo A, et al.
    • Journal Title

      Experimental Hematology 32・12

      Pages: 1246-1254

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Journal Article] CD19-targeting liposomes containing imatinib efficiently kill Phila-delphia chromosome-positive acute lymphoblastic leukemia cells2004

    • Author(s)
      Harata M, Soda Y, Tojo A, et al.
    • Journal Title

      Blood 104-5

      Pages: 1442-1449

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Unrelated cord blood transplantation after myeloablative conditioning in patients over the age of 45 years2004

    • Author(s)
      Ooi J, Soda Y, Tojo A, et al.
    • Journal Title

      British Journal of Haematology 126-5

      Pages: 711-714

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Hematopoietic activity of common marmoset CD34 cells isolated by a novel monoclonal antibody MA242004

    • Author(s)
      Izawa K, Soda Y, Tojo A, et al.
    • Journal Title

      Experimental Hematology 32-9

      Pages: 843-851

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Phase I study of autologous tumor vaccines transduced with the GM-CSF gene (GVAX^<【○!R】>) in four patients with Stage IV renal cell cancer in Japan : clinical and immunological findings2004

    • Author(s)
      Tani K, Soda Y, Asano S, et al.
    • Journal Title

      Molecular Therapy 10-3

      Pages: 799-816

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Anti-NK cell treatment induces stable mixed chimerism in MHC-mismatched, T cell-depleted, nonmyeloablative bone marrow transplantation2004

    • Author(s)
      Cho SG, Soda Y, Tojo A, et al.
    • Journal Title

      Experimental Hematology 32-12

      Pages: 1246-1254

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] The synthetic peptide derived from the NH2-terminal extracellular region of an orphan G protein-coupled receptor, GPR1, preferentially inhibits infection of X4 HIV-12004

    • Author(s)
      Jinno-Oue A, Shimizu N, Soda Y, et al.
    • Journal Title

      Journal of Biological Chemistry 280-35

      Pages: 30924-30934

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A novel Maxizyme vector targeting a bcr-abl fusion gene induced specific cell death in Philadelphia chromosome-positive phoblastic acute leukemia2004

    • Author(s)
      Soda Y, Tani K, Tojo A, et al.
    • Journal Title

      Blood 104・2

      Pages: 356-363

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phase I study of autologous tumor vaccines transduced with the GM-CSF gene (GVAX^<【○!R】>) in four patients with Stage IV renal cell cancer in Japan : clinical and immunological findings2004

    • Author(s)
      Tani K, Soda Y, Asano S, et al.
    • Journal Title

      Molecular Therapy 10・3

      Pages: 799-816

    • Related Report
      2004 Annual Research Report
  • [Journal Article] p51/p63, a novel p53 homologue, potentiates p53 activity and is a human cancer gene therapy candidate

    • Author(s)
      Kunisaki R, Ikawa S, Soda Y, et al.
    • Journal Title

      Journal of Gene Medicine (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary

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Published: 2004-04-01   Modified: 2016-04-21  

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