Intramuscular Transplantation of G-CSF-Mobilized CD34+ Cells in Patients With Critical Limb Ischemia: A Phase I/IIa, Multicenter, Single-Blinded, Dose-Escalation Clinical Trial§

Authors

  • Atsuhiko Kawamoto,

    Corresponding author
    1. Division of Vascular Regeneration Therapy, Department of Translational ResearchInstitute of Biomedical Research and Innovation, Kobe, Japan
    2. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    • Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation, 2-2 Minatojima Minamimachi, Chuo-Ku, Kobe 650-0047, Japan
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    • Telephone: 81-78-304-5772; Fax: 81-78-304-5263

  • Minako Katayama,

    1. Division of Vascular Regeneration Therapy, Department of Translational ResearchInstitute of Biomedical Research and Innovation, Kobe, Japan
    2. Department of Clinical Research PromotionInstitute of Biomedical Research and Innovation, Kobe, Japan
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  • Nobuhiro Handa,

    1. Department of Cardiovascular SurgeryKobe City Medical Center General Hospital, Kobe, Japan
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  • Makoto Kinoshita,

    1. Division of Vascular Regeneration Therapy, Department of Translational ResearchInstitute of Biomedical Research and Innovation, Kobe, Japan
    2. Department of CardiologyKobe City Medical Center General Hospital, Kobe, Japan
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  • Haruna Takano,

    1. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
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  • Miki Horii,

    1. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
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  • Kazuyo Sadamoto,

    1. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
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  • Ayumi Yokoyama,

    1. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
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  • Takeharu Yamanaka,

    1. Translational Research Informatics Center, Kobe, Japan
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  • Rie Onodera,

    1. Translational Research Informatics Center, Kobe, Japan
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  • Akiko Kuroda,

    1. Department of Clinical Research PromotionInstitute of Biomedical Research and Innovation, Kobe, Japan
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  • Rie Baba,

    1. Clinical Laboratory, Institute of Biomedical Research and Innovation, Kobe, Japan
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  • Yuichiro Kaneko,

    1. Clinical Laboratory, Institute of Biomedical Research and Innovation, Kobe, Japan
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  • Tomio Tsukie,

    1. Department of Plastic Surgery, Kobe City Medical Center General Hospital, Kobe, Japan
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  • Yasuo Kurimoto,

    1. Department of Ophthalmology, Kobe City Medical Center General Hospital, Kobe, Japan
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  • Yukikatsu Okada,

    1. Department of Cardiovascular SurgeryKobe City Medical Center General Hospital, Kobe, Japan
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  • Yasuki Kihara,

    1. Department of CardiologyKobe City Medical Center General Hospital, Kobe, Japan
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  • Shigefumi Morioka,

    1. Department of CardiologyKobe City Medical Center General Hospital, Kobe, Japan
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  • Masanori Fukushima,

    1. Translational Research Informatics Center, Kobe, Japan
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  • Takayuki Asahara

    Corresponding author
    1. Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, Kobe, Japan
    2. Department of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Japan
    • Laboratory for Stem Cell Translational Research, Institute of Biomedical Research and Innovation, 2-2 Minatojima Minamimachi, Chuo-Ku, Kobe 650-0047, Japan
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    • Telephone: 81-78-304-5772; Fax: 81-78-304-5263


  • Author contributions: A. Kawamoto: conception and design, provision of study material or patients, collection and/or assembly of data, manuscript writing; M.K.: conception and design, collection and/or assembly of data; N.H.: provision of study material or patients; M.K.: collection and/or assembly of data; H.T.: collection and/or assembly of data; M.H.: collection and/or assembly of data; K.S.: collection and/or assembly of data; A.Y.: collection and/or assembly of data; T.Y.: final approval of manuscript; R.O.: data analysis and interpretation; A. Kuroda: collection and/or assembly of data; R.B.: collection and/or assembly of data; Y. Kaneko: collection and/or assembly of data; T.T.: provision of study material or patients; Y. Kurimoto: collection and/or assembly of data; Y.O.: provision of study material or patients; Y. Kihara: provision of study material or patients; S.M.: provision of study material or patients; M.F.: conception and design, data analysis and interpretation; T.A.: conception and design, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLS EXPRESS August 26, 2009.

Abstract

A number of preclinical studies have indicated the therapeutic potential of endothelial progenitor cells for vascular regeneration in ischemic diseases. A phase I/IIa clinical trial of transplantation of autologous CD34+ cells, the endothelial and hematopoietic progenitor-enriched fraction, was performed in no-option patients with atherosclerotic peripheral artery disease or Buerger's disease with critical limb ischemia (CLI). CD34+ cells were isolated from the G-CSF-mobilized apheresis product using a magnetic cell sorting system. CD34+ cells (105/kg, n = 6; 5 × 105/kg, n = 8; or 106/kg, n = 3) were injected i.m. into the leg with more severe ischemia. The Efficacy Score, representing changes in the toe brachial pressure index (TBPI), Wong-Baker FACES pain rating scale, and total walking distance 12 weeks after cell transplantation, the primary endpoint, was positive, indicating improvement in limb ischemia in all patients, although no significant dose-response relationship was observed. During the 12-week observation after cell therapy, the Wong-Baker FACES pain rating scale, TBPI, transcutaneous partial oxygen pressure, total or pain-free walking distance, and ulcer size serially improved in all patients. No death or major amputation occurred, and severe adverse events were rare, although mild to moderate events relating to G-CSF and leukapheresis were frequent during the 12-week follow-up. In conclusion, the outcomes of this prospective clinical study indicate the safety and feasibility of CD34+ cell therapy in patients with CLI. Favorable trends in efficacy parameters encourage a randomized and controlled trial in the future. STEM CELLS 2009;27:2857–2864

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