Effect of Progenitor Cell Mobilization With Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Peripheral Artery Disease

Abstract

IMPORTANCE Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown.OBJECTIVE To investigate whether therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) improves exercise capacity in patients with intermittent claudication. DESIGN, SETTING, AND PARTICIPANTSIn a phase 2 double-blind, placebo-controlled study, 159 patients (median [SD] age, 64 [8] years; 87% male, 37% with diabetes) with intermittent claudication were enrolled at medical centers affiliated with Emory University in Atlanta, Georgia, between January 2010 and July 2012.INTERVENTIONS Participants were randomized (1:1) to received 4 weeks of subcutaneous injections of GM-CSF (leukine), 500 μg/day 3 times a week, or placebo. Both groups were encouraged to walk to claudication daily. MAIN OUTCOMES AND MEASURESThe primary outcome was peak treadmill walking time (PWT) at 3 months. Secondary outcomes were PWT at 6 months and changes in circulating PC levels, ankle brachial index (ABI), and walking impairment questionnaire (WIQ) and 36-item Short-Form Health Survey (SF-36) scores. RESULTSOf the 159 patients randomized, 80 were assigned to the GM-CSF group. The mean (SD) PWT at 3 months increased in the GM-CSF group from 296 (151) seconds to 405 (248) seconds (mean change, 109 seconds [95% CI, 67 to 151]) and in the placebo group from 308 (161) seconds to 376 (182) seconds (change of 56 seconds [95% CI, 14 to 98]), but this difference was not significant (mean difference in change in PWT, 53 seconds [95% CI, −6 to 112], P = .08). At 3 months, compared with placebo, GM-CSF improved the physical functioning subscore of the SF-36 questionnaire by 11.4 (95% CI, 6.7 to 16.1) vs 4.8 (95% CI, −0.1 to 9.6), with a mean difference in change for GM-CSF vs placebo of 7.5 (95% CI, 1.0 to 14.0; P = .03). Similarly, the distance score of the WIQ improved by 12.5 (95% CI, 6.4 to 18.7) vs 4.8 (95% CI, −0.2 to 9.8) with GM-CSF compared with placebo (mean difference in change, 7.9 [95% CI, 0.2 to 15.7], P = .047). There were no significant differences in the ABI, WIQ distance and speed scores, claudication onset time, or mental or physical component scores of the SF-36 between the groups.CONCLUSIONS AND RELEVANCE Therapy with GM-CSF 3 times a week did not improve treadmill walking performance at the 3-month follow-up. The improvements in some secondary outcomes with GM-CSF suggest that it may warrant further study in patients with claudication.

Stem Cell Imaging: From Bench to Bedside

“…Based on these promising results, investigators have launched several Phase I and II studies to evaluate the safety and efficacy of stem cell therapies for the treatment of ischemic heart disease (Bolli et al, 2011; Hare et al, 2012; Heldman et al, 2014; Perin et al, 2012; Traverse et al, 2011; Traverse et al, 2012), peripheral vascular disease (Poole et al, 2013), spinal cord injury (Mothe and Tator, 2012), multiple sclerosis (Uccelli et al, 2011), and stroke (Bang et al, 2005; Kondziolka et al, 2005; Lee et al, 2010). While safety has been clearly demonstrated, efficacy remains more elusive (Clifford et al, 2012; Fadini et al, 2010).…”

Ischemia-related changes in circulating stem and progenitor cells and associated clinical characteristics in peripheral artery disease

“…Most of these studies showed no benefits of the SPC mobilizing agents for improving outcomes in PAD. The largest randomized trial to test the ability of GM-CSF to improve walking performance in people with PAD showed no benefit for the primary outcome measure of improved treadmill walking performance 25 . The ongoing PROPEL trial will test the ability of GM-CSF combined with the ischemic stimulus of supervised treadmill exercise to improve walking performance in people with PAD 16 .…”

Circulating Progenitor Cells is Linked to Cognitive Decline in Healthy Adults

“…Progenitor cell-directed therapies may offer a new target for cognitive impairment prevention. 32,33 …”