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Clinical Trials, U.S.: Peripheral Vascular Disease

Clinical Trials, U.S.: Peripheral Vascular Disease

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Clinical Trials, U.S.: Peripheral Vascular Disease

Peripheral artery disease (PAD) is an occlusive disease specific to arteries of the lower extremities and is often a serious condition that can result in the need for revascularization or surgery. It is usually caused by a buildup of plaque in the lining of the vessel or a blood clot. This buildup eventually leads to a reduction in blood flow that will deprive the nearby tissues of oxygen. Symptoms can range from intermittent claudication (difficulty walking) to the development of chronic limb ischemia (CLI). Over 10 million Americans suffer from various stages of the disease. About 20 percent to 30 percent of CLI patients are poor candidates for revascularization or surgery; thus, it is important to find alternative methods to improve tissue perfusion in this group of patients. Stem cell therapy has emerged as a viable option.

Stem cells are undifferentiated cells that have the potential to become a specific cell type under appropriate conditions. These cells are present either during development of the embryo, called embryonic stem cells (ESC), or as adult stem cells (ASC), which reside in specific organ tissues. Embryonic stem cells are pluripotent because they have the potential to become virtually any type of cell. Adult stem cells are multipotent, and they are able to differentiate into a limited number of cell types. However, scientists have discovered that some adult cells can be induced into a pluripotent (iPC) state, given the proper environment. Some examples of adult cells include endothelial progenitor cells (EPC) and bone marrow mononuclear cells (BMMNC). Early clinical studies have primarily aimed at measuring parameters indicating improvement in tissue perfusion, oxygen levels (TcPO₂), ankle brachial index (ABI), and limb salvage. Pain-free walking or distance walked has also been used to indicate improvement in tissue perfusion, facilitated by neocollateralization, or the growth of new blood vessels in the damaged area. Claudication is accessed using the Fontaine classification (I to IV) or Rutherford score (0–6); lower scores represent less severity than higher scores that represent CLI stage.

Clinical Stem Cell Therapy Trials and PAD

Recent clinical trials in the United States have been conducted on autologous (patient’s own) BMMNC administration with outcome measures of collateral formation, improved ABI, TcPO₂, and limb salvage. In the M. D. Iafarati et al. study, patients achieved improvement in ABI, TcPO₂, and were able to preserve more limbs, compared to E. Benoit et al., R. J. Powell et al., or D. W. Losordo et al. The latter did not demonstrate improvement in ABI or TcPO₂ levels. The M. P. Murphy et al. study reported an improvement in ABI only using autologous BMMNCs. A Phase II trial by Powell et al. used an expanded multicellular cell population (Ixmyelocel-T) mixed with the patient’s BMMNC sample. ABI did not improve but limb salvage was observed at 12 month’s follow-up.

Losordo et al. used enriched auto-CD34+ BMMNCs, which were injected into the ischemic limb. Patients were given a low dose, high dose, or placebo. Overall, there was no improvement observed for ABI or TcPO₂, but there were fewer amputations among the treatment groups compared to placebo and improved Rutherford scores. Of note, patients with the highest dose of CD34+ cells had greater improvement compared to the low dose group.

E. C. Perin and colleagues investigated the effectiveness of a new subpopulation of BMMNCs, aldehyde dehydrogenase-bright (ALDHbr) cells, which contain vasculogenic and myogenic properties and have been shown to prevent cell death. Improved ABI and Rutherford scores were observed at 6 and 12 weeks, compared to baseline, in patients who received the enriched ALDHbr mixture. Patients who had received BMMNCs only showed improvement in ABI at 12 weeks. Another unique study by G. P. Lasala and colleagues investigated the effect of combined cell therapy: BMMSC and BMMNC. There were improvements in ABI and walking time, and the administration of the combination was declared safe.

Future Direction

Currently, a variety of cell types are being investigated to identify the most effective cells for angiogenesis. Under investigation are endometrial regenerative cells (ERC), which are mesenchymal cells isolated from menstrual blood. Adipose-derived stromal cells are being used to coat an expanded polytetrafluorethlene vascular graft (ePTFE) to replace damaged vessels.

In summary, clinical studies that focus on using stem cells for improved perfusion and limb preservation in severe PAD have shown that these therapies are safe to use. Many questions still remain to be answered concerning the most beneficial type, optimal dosage of cells, duration of therapy, and optimal route of administration. Tantamount to obtaining these answers, clinical scientists must conduct randomized, controlled clinical trials that are adequately powered.

Mandy McBroom

University of Texas Southwestern Medical Center

See Also: Blood Adult Stem Cell: Current Research on Isolation or Production of Therapeutic Cells; iPS, Methods to Produce; Mesenchymal: Existing or Potential Regenerative Medicine Strategies; Vascular Stem Cell.

Further Readings

Benoit, E., T. F. O’Donnell, M. D. Iafrati, E. Asher, et al. “The Role of Amputation as an Outcome Measure in Cellular Therapy for Critical Limb Ischemia: Implications for Clinical Trial Design.” Journal of Translational Medicine, v.9/165 (2011).

Corbellis, G., A. Silvestroni, S. Lillo, G. Sica, et al. “Long-Term Effects of Repeated Autologous Transplantation of Bone Marrow Cells in Patients Affected by Peripheral Artery Disease.” Bone Marrow Transplant, v. 42/10 (2008).

Iafrati, M. D., J. W. Hallett, G. Geils, G. Pearl, et al. “Early Results and Lessons Learned From a Multicenter Randomized, Double-Blind Trial of Bone Marrow Aspirate Concentrate in Critical Limb Ischemia.” Journal of Vascular Surgery, v.54/6 (2011).

Lasala, G. P., J. A. Silva, and J. J. Minquell. “Therapeutic Angiogenesis in Patients With Severe Limb Ischemia by Transplantation of a Combination Stem Cell Product.” Journal of Thoracic and Cardiovascular Surgery, v.144/2 (2012).

Loffredo, F. and R. T. Lee. “Therapeutic Vasculogenesis: It Takes Two.” Circulation Research, v.103/2(2008).

Losordo, D. W., M. R. Kibbe, F. Mendelsohn, W. Marston, et al. “A Randomized, Controlled Pilot Study of Autologous CD34+ Cell Therapy for Critical Limb Ischemia.” Circulation: Cardiovascular Interventions, v.5/6 (2012).

Murphy, M. P., J. H. Lawson, B. M. Rapp, M. C. Dalsing, et al. “Autologous Bone Marrow Mononuclear Cell Therapy Is Safe and Promotes Amputation-Free Survival in Patients With Critical Limb Ischemia.” Journal of Vascular Surgery, v.53/6 (2011).

Perin, E. C., G. Silva, A. Gahremanpour, J. Canales, et al. “A Randomized, Controlled Study of Autologous Therapy With Bone Marrow-Derived Aldehyde Dehydrogenase Bright Cells in Patients With Critical Limb Ischemia.” Catheterization and Cardiovascular Interventions, v.78/7 (2010).

Powell, R. J., A. J. Comerota, S. A. Berceli, R. Guzman, et al. “Interim Analysis Results From the RESTORE-CLI, a Randomized, Double-Blind Multicenter Phase II Trial Comparing Expanded Autologous Bone Marrow-Derived Tissue Repair Cells and Placebo in Patients With Critical Limb Ischemia.” Journal of Vascular Surgery, v.54/4 (2011).

Powell, R. J., W. A. Marston, S. A. Berceli, R. Guzman, et al. “Cellular Therapy With Ixmyocelocel-T to Treat Critical Limb Ischemia: The Randomized, Double-Blind, Placebo Controlled RESTORE-CLI Trial.” Molecular Therapy, v.20/6 (2012).