A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia

Abstract

Background Critical limb ischemia (CLI) portends a risk of major amputation of 25-35% within 1 year of diagnosis. Pre-clinical studies provide evidence that intramuscular injection of autologous CD34+ cells improve limb perfusion and reduce amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk CLI who were poor or non-candidates for surgical or percutaneous revascularization (ACT34-CLI). Methods and Results Twenty-eight CLI subjects were randomized and treated: 7 to 1×105 (low-dose) and 9 to 1×106 (high-dose) autologous CD34+ cells/kg; 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months post-injection 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends towards improved amputation free survival at 6 and 12 months. No adverse safety signal was associated with cell administration. Conclusions This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later phase clinical trials.

A Five-Year Study of the Efficacy of Purified CD34+ Cell Therapy for Angiitis-Induced No-Option Critical Limb Ischemia

“…Second, the outcomes in the three ASO patients we reported on in our pilot study appeared to be poor 4. All of the ASO patients underwent major amputations within 3 months after PuCeT, similar to the disappointing results from ASO patients in other studies 2, 8. In contrast, the outcomes of AICLI patients showed extreme promise.…”

“…As one of the stem cell therapies, PuCeT has demonstrated encouraging outcomes 2, 3. Similarly, in our pilot study conducted from 2009 to 2011, PuCeT demonstrated favorable early outcomes in AICLI 4.…”

“…Many studies using different methods, such as vascular endothelial growth factor (VEGF)‐related gene transfer 6, 7, bone‐marrow mononuclear cell (BMMNC) 8, 9, 10, 11, 12, PBMNC 13, 14, 15, 16, 17, 18, or CD34+ cell 2, 3, 4 transplantation, have been completed and have proven their safety and efficacy. The long‐term outcome after CD34+ cell therapy in CLI patients was already reported by Kinoshita et al in 2012 19.…”

Intravenous Administration of Endothelial Colony-Forming Cells Overexpressing Integrin β1 Augments Angiogenesis in Ischemic Legs

“…The CD34 + stem cell fraction of adult human peripheral blood has already been used in two preclinical trials of therapeutic angiogenesis for PAD. One trial showed significant improvements in the efficacy scores (toe-brachial pressure index, pain scale, and total walking distance); however, the other study showed no effect on amputation rates [25,26]. Neither trial reported any treatment-associated adverse events; thus, the safety and feasibility of ECFC-based therapy can be considered established.…”

Circulating Endothelial Progenitor Cells in Crohn’s Disease: An EPiC in the Making?

“…Studies in the last several years suggest that endothelial impairment substantially contributes to the onset and progression of and recovery from inflammatory conditions [1]. EPCs, derived from bone marrow hematopoietic stem cells, (HSCs) have the capability to migrate to the site of endothelial damage through the peripheral circulation and have been used to treat several inflammatory diseases, ischemic limb disease, peripheral vascular disease, and coronary heart disease [6][7][8].…”