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.
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.
Kawamoto
Atsuhiko
A
Division of Vascular Regeneration Therapy, Department of Translational Research, Institute of Biomedical Research and Innovation, Kobe 650-0047, Japan. kawamoto@fbri.org
Katayama
Minako
M
Handa
Nobuhiro
N
Kinoshita
Makoto
M
Takano
Haruna
H
Horii
Miki
M
Sadamoto
Kazuyo
K
Yokoyama
Ayumi
A
Yamanaka
Takeharu
T
Onodera
Rie
R
Kuroda
Akiko
A
Baba
Rie
R
Kaneko
Yuichiro
Y
Tsukie
Tomio
T
Kurimoto
Yasuo
Y
Okada
Yukikatsu
Y
Kihara
Yasuki
Y
Morioka
Shigefumi
S
Fukushima
Masanori
M
Asahara
Takayuki
T
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
D018952:Antigens, CD34; D016179:Granulocyte Colony-Stimulating Factor