Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) Trial

Abstract

Conclusions: Local injection of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells (in the dosage and manner described) into the thigh and calf of patients with claudication does not improve peak walking disease (PWT) or magnetic resonance imaging (MRI) capillary perfusion nor were there demonstrated quality of life (QOL) improvements. In patients with completely occluded superficial femoral arteries, the number of collateral arteries did increase with ALDHbr cell injection on post hoc analysis, which suggests a potential benefit in those with more advanced disease.Summary: This National Heart Lung and Blood Institute-sponsored "Patients with Intermittent Claudication with ALDH Bright Cells" (PACE) study is a phase II randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of administration of ALDHbr cells vs cell-free placebo in individuals with peripheral vascular disease (PAD) and intermittent claudication. It is important to note that PACE was not designed to serve as a pivotal PAD cell therapy outcomes trial because the cell type, dosage, timing of dosing, local physiologic mechanisms, and treatment effect of potential cell types are unknown. Rather, PACE was designed as a phase II investigation that would (1) provide unbiased treatment effects for each of four primary end points, and (2) evaluate a wide set of pre hoc defined physiologic relationships that could help to direct claudication research. These secondary exploratory goals were equal in importance to the evaluation of any primary clinical end point. The change in four primary end points evaluated at 6 months were (1) peak walking time (PWT), (2) number of collateral arteries (collateral count) in the treated limb determined by magnetic resonance imaging (MRI), (3) popliteal artery peak hyperemic flow measured by MRI, and (4) MRI measurement of limb perfusion. The protocol also specified an evaluation of the relationships between MRI measures of capillary count, large artery (popliteal) flow, and capillary perfusion, with clinically relevant measurements of limb function evaluated using traditional exercise testing. Patients were aged >40 years, had claudication symptoms greater in one leg (index leg), with no inflow disease and with a significant (>50%) stenosis/occlusion of at least one infrainguinal arterial segment (any or all of superficial femoral artery, popliteal artery, or infrapopliteal arteries). Patients with prior bypass were included only if the bypass had failed and the other conditions existed. Claudication severity, patient-reported health status and QOL were evaluated by the San Diego Claudication Questionnaire (SDCQ), the Walking Impairment Questionnaire (WIQ), and Peripheral Arterial Questionnaire (PAQ). Baseline ankle-brachial index (ABI) and Gardner-Skinner exercise treadmill testing were performed. The latter documented that the index leg claudication was limited to #12 minutes. MRI angiography was performed to document anatomy and to conduct resting and postocclusi...

Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies—Statement From ATVB Council

“…124 This occurs even though there are no data to suggest that women respond differently to therapies such as supervised exercise, cilostazol, or other investigational agents. 117,122,125 Women appear to be selected for surgical intervention less frequently than men, 126 but have more post-procedural complications when they do undergo surgery. For example, women have been reported to experience higher rates of vascular access site occlusion and groin hematoma, and may have lower long term graft patency rates after intervention.…”

Tissue-specific angiogenic and invasive properties of human neonatal thymus and bone MSCs: Role of SLIT3-ROBO1

“…Mesenchymal stem/stromal cells (MSCs) are located in the perivascular region, can be isolated from a variety of tissues, and are being evaluated as proangiogenic and proregenerative therapies in numerous clinical trials. [1][2][3][4][5][6][7][8] Although endothelial cells have been recently recognized to possess tissue-specific properties, the influence of tissue origin on MSC therapeutic effects is poorly understood. 9,10 The ability of MSCs to migrate to damaged tissues to exert its proregenerative, anti-inflammatory, and proangiogenic effects also influences their therapeutic potential.…”

Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic effect of ALDH bright cell on peripheral ischemia

“…Among them, the cytosolic ALDH1A sub-family, which comprises the primary ALDHs (ALDH1A1/-1A2/-1A3), is known as the major component of ALDH br cells [2] . The safety and efficiency of autologous ALDH br cells therapy have been proved by randomized, double-blind pilot study in patients with chronic myocardial ischemia [3] and critical limb ischemia [4] , [5] . Robust hematopoietic repopulating function [6] and angiogenesis capacity [7] were also revealed in the immunodeficient mice post administration of ALDH br cells.…”