title: 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.
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 (10(5)/kg, n = 6; 5 x 10(5)/kg, n = 8; or 10(6)/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.
authors.affiliation: Division of Vascular Regeneration Therapy, Department of Translational Research, Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan. kawamoto@fbri.org
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kawamoto
authors.forename: Minako
authors.initials: M
authors.lastname: Katayama
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Handa
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Haruna
authors.initials: H
authors.lastname: Takano
authors.forename: Miki
authors.initials: M
authors.lastname: Horii
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Sadamoto
authors.forename: Ayumi
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.forename: Rie
authors.initials: R
authors.lastname: Onodera
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuroda
authors.forename: Rie
authors.initials: R
authors.lastname: Baba
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kaneko
authors.forename: Tomio
authors.initials: T
authors.lastname: Tsukie
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kurimoto
authors.forename: Yukikatsu
authors.initials: Y
authors.lastname: Okada
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Shigefumi
authors.initials: S
authors.lastname: Morioka
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Asahara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy / Q000009:adverse effects / Q000379:methods*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000628:therapy*; D007866:Leg / Q000473:pathology*; D008297:Male; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014182:Transplantation, Autologous; D016896:Treatment Outcome
chemical_list: D018952:Antigens, CD34; D016179:Granulocyte Colony-Stimulating Factor