Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease

Abstract

Background Atherosclerotic peripheral artery disease (PAD) affects 8–12% of Americans over 65 and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE is an NHLBI-sponsored, randomized, double-blind, placebo-controlled phase 2, exploratory clinical trial designed to assess safety and efficacy of autologous bone marrow–derived aldehyde dehydrogenase bright (ALDHbr) cells in PAD patients and to explore associated claudication physiologic mechanisms. Methods All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by ten injections into the thigh and calf of the index leg. The co-primary endpoints were: change from baseline to six months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging (MRI); as well as safety. Results A total of 82 patients with claudication and infra-inguinal PAD were randomized at nine sites, of which 78 had analyzable data (57 male, 21 female; mean age 66±9 years). The mean differences in the change over six months between study groups for PWT (mean ± standard error of the mean [SEM]) (0.9±0.8 minutes; 95% CI −0.6 to 2.5; p=0.238), collateral count (0.9±0.6 arteries; 95% CI −0.2 to 2.1; p=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/sec; 95% CI −0.8 to 0.8; p=0.978), and capillary perfusion (−0.2±0.6%; 95% CI −1.3 to 0.9; p=0.752) were not significant. Additionally, there were no significant differences for the secondary endpoints, including quality of life measures. There were no adverse safety outcomes. Correlative relationships between MRI measures and PWT were not significant. A post-hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI 0.1 to 2.9; p=0.047) in participants with completely occluded femoral arteries. Conclusions ALDHbr cell administration did not improve PWT or MR outcomes, and the changes in PWT were not associated with the anatomic or physiologic MRI endpoints. Future PAD cell therapy investigational trial design may be informed by new anatomic and perfusion insights.

Lower extremity arterial disease in patients with diabetes: a contemporary narrative review

“…Further high-quality placebo-controlled randomized trials are needed to confirm the safety and the efficiency of autologous cell therapy in patients with LEAD. Of note, a recent placebo-compared RCT (Patients With Intermittent Claudication Injected With ALDH Bright Cells (PACE)) did not support the use of cell therapy in patients with LEAD [ 127 ]. PACE trial has not shown improvement in peak walking time, collateral count, peak hyperaemic popliteal flow, and capillary perfusion in patients with LEAD treated by autologous bone marrow-derived aldehyde dehydrogenase bright cells.…”

Foreskin-derived mesenchymal stromal cells with aldehyde dehydrogenase activity: isolation and gene profiling

“…The expression of HIF1α and GLUT1 genes was higher in ALDH + cells confirming their importance for cell-response to hypoxia. Thus, the therapeutic efficiency of ALDH + cells was observed in patients with chronic myocardial ischemia and critical limb ischemia [ 71 , 72 ].…”

Near‐Infrared IIb Fluorescence Imaging of Vascular Regeneration with Dynamic Tissue Perfusion Measurement and High Spatial Resolution

“…Patients with a severe form of PAD have critical limb ischemia and are at risk of limb amputation. Biological approaches to treat PAD, including cell or protein therapies have shown only moderate benefit in late‐phase clinical trials . Accordingly, there is a great demand for new biological or pharmacological therapies that can improve vascular generation and restore blood perfusion to the site of limb ischemia.…”