A Randomized, Controlled Study of Autologous Therapy With Bone Marrow–Derived Aldehyde Dehydrogenase Bright Cells in Patients With Critical Limb Ischemia Emerson C. Perin, 1 * MD, PhD, Guilherme Silva, 1 MD, Amir Gahremanpour, 1 MD, John Canales, 1 MD , Yi Zheng, 1 MD, Maria G. Cabreira-Hansen, 1 PhD, Farrell Mendelsohn, 2 MD, Nicolas Chronos, 3 MD, Rebecca Haley, 4 MD, James T. Willerson, 1,5 MD, and Brian H. Annex, 6 MD Objectives: The safety and efficacy of direct intramuscular injections of aldehyde dehydro- genase bright (ALDH br ) cells isolated from autologous bone marrow mononuclear cells (ABMMNCs) and ABMMNCs were studied in patients with critical limb ischemia (CLI) who were not eligible for percutaneous or surgical revascularization. Background: Many CLI patients are not candidates for current revascularization procedures, and amputation rates are high in these patients. Cell therapy may be a viable option for CLI patients. Methods: Safety was the primary objective and was evaluated by occurrence of adverse events. Effi- cacy, the secondary objective, was evaluated by assessment of Rutherford category, ankle- brachial index (ABI), transcutaneous partial pressure of oxygen (TcPO 2 ), quality of life, and pain. Results: ALDH br cells and ABMMNCs were successfully administered to all patients. No therapy-related serious adverse events occurred. Patients treated with ALDH br cells (n 5 11) showed significant improvements in Rutherford category from baseline to 12 weeks (mean, 4.09 6 0.30 to 3.46 6 1.04; P 5 0.05) and in ABI at 6 (mean, 0.22 6 0.19 to 0.30 6 0.24; P 5 0.02), and 12 weeks (mean, 0.36 6 0.18; P 5 0.03) compared with baseline. Patients in the ABMMNC group (n 5 10) showed no significant improvements at 6 or 12 weeks in Ruth- erford category but did show improvement in ABI from baseline to 12 weeks (0.38 6 0.06 to 0.52 6 0.16; P 5 0.03). No significant changes from baseline were noted in ischemic ulcer grade or TcPO 2 in either group. Conclusions: Administration of autologous ALDH br cells appears to be safe and warrants further study in patients with CLI. V C 2011 Wiley Periodicals, Inc. Key words: limb ischemia; neoangiogenesis; autologous bone marrow mononuclear cells; aldehyde dehydrogenase bright cells; peripheral arterial disease INTRODUCTION Critical limb ischemia (CLI) is the most severe man- ifestation of peripheral arterial disease (PAD) and is associated with death, amputation, and a quality of life similar to that of patients with terminal cancer [1,2]. The reduction in arterial circulation is so severe that viability of the limb is threatened. CLI is characterized by the presence of ischemic pain at rest that may be accompanied by tissue loss [3,4]. Despite advances in percutaneous and surgical revascularization techniques, up to 40% of patients are not candidates for revascular- ization at initial presentation [4]. Amputation rates in patients not suitable for revascularization are reported to be up to 30–50% at 1 year [5,6]. In patients for whom revascularization is not an option, novel therapies are needed. Recent clinical studies have demonstrated that autologous adult stem cells may benefit these patients by improving perfusion 1 Stem Cell Center, Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas 2 Cardiology PC, Birmingham, Alabama 3 Saint Joseph’s Research Institute, Atlanta, Georgia 4 Duke University, Durham, North Carolina 5 Adult Cardiology, Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas 6 University of Virginia, Charlottesville, Virginia Conflict of Interest: Nothing to report Grant sponsor: Aldagen, Inc., Durham, NC *Correspondence to: Emerson C. Perin, MD, PhD, Texas Heart Insti- tute, Stem Cell Center, St. Luke’s Episcopal Hospital, 6624 Fannin, Suite 2220, Houston, TX 77030. E-mail: eperin@bluegate.com Received 26 July 2010; Revision accepted 17 February 2011 DOI 10.1002/ccd.23066 Published online 18 May 2011 in Wiley Online Library (wileyonlinelibrary.com) V C 2011 Wiley Periodicals, Inc. Catheterization and Cardiovascular Interventions 78:1060–1067 (2011)