No abstract

Therapeutic angiogenesis with phVEGF165 gene transfer, if instituted before the development of forefoot gangrene, may provide a novel therapy for patients with advanced Buerger's disease that is unresponsive to standard medical or surgical treatment methods.

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.

These findings support the notion that in-stent restenosis results from SMC hyperplasia and suggest that adjunctive therapies designed to inhibit SMC proliferation may further enhance the utility of endovascular stents.