Stem Cell Treatments for Critical Limb Ischaemia
Stem cell treatments for critical limb ischaemia have followed two general paths; one of stem cell injection to create new blood vessel growth (angiogenesis), and one of using stem cells to create blood vessels for grafting in vascular surgery. Preliminary studies have shown that the introduction of endothelial progenitor cells (EPCs) into the back of the leg can recruit bone marrow stem cells to further facilitate angiogenesis and improve perfusion to the area (Asahara, et al, 1999). There appears to be considerable individual differences in patient response to such treatment however, with some showing little sign of bone marrow stem cell recruitment following treatment and others experiencing significant relief from CLI most likely due to the mobilization of mesenchymal stem cells from the bone marrow.
Forcing Stem Cells into Action
In light of such observations, some researchers, such as those at CellMedicine, are now investigating the use of combined therapy using stem cell injections and medications to force stem cells out of the bone marrow and into peripheral circulation. A potential problem with such a strategy is that the very factor that allows the release of the stem cells into the blood (a CXCR4 antagonist) is the same factor which would be used by the injected stem cells to attract the bone marrow cells to the ischaemic site. The stem cells may be mobilized but they are not necessarily going to end up where the clinicians would like them to be.
Stem Cell Trials for CLI
One study by Miyamoto (et al, 2006) has numerous methodological issues, including a lack of control group, blinding, possible confounding variables, and a very small sample size, but nonetheless presents some evidence of the successful use of bone marrow-derived mononuclear cells to treat a particular subset of patients with CLI, namely those with TAO. The main outcome was a reduction in pain experienced by the patients, and improved healing of skin lesions although other factors, such as smoking cessation could account for these effects. Further research carried out by Rey (et al, 2009) has demonstrated improved blood flow, movement, and decreased tissue death and amputation necessity in mice models using stem cells.
Genes and Stem Cell Therapy for CLI
One of the researchers in Rey’s study, Semenza (2008), previously worked on generating a virus that carries the gene which encodes for the active form of the HIF-1 protein, responsible for facilitating angiogenesis. Using the genetic technique the researchers have treated diabetic and non-diabetic mice with induced CLI and discovered that after three weeks those mice receiving the HIF-1 virus had 85% recovery of blood flow compared to 24% in the placebo group. A combination of the gene therapy and bone marrow-derived stem cells injected into the legs of mice with induced ischaemia resulted in a reduction in those requiring amputation in the treatment group compared to controls. The gene appears to not only help the stem cells home in on the ischaemic limb but also to stay there after arrival.
Dangers of Stem Cell Therapy for CLI
Rather troubling for researchers, and patients, in this area of stem cell treatment is the incidence of sudden death in one participant in the Miyamoto trial, for which there was no clear explanation, and the potential for stem cells to behave in ways not yet clearly understood. It is possible that mobilized bone marrow stem cells may target both arterial and venous vessels, that the formation of new arterial plaque may be accelerated in such treatments, and that plaque may be destabilized causing further ischaemia in smaller blood vessels after therapy. Preclinical models have noted such effects and further research is required to fully assess the risks and benefits of stem cell therapy for critical limb ischaemia (Hirsch, 2006).
Diabetic Foot Ulcers, CLI, and Clinical Trial Results
The results of a number of clinical trials into the use of stem cells for CLI are eagerly anticipated in 2011, including NCT00616980, and NCT01065337 which looked specifically at the use of stem cell injections to treat diabetic foot ulcers. A study by Aldagen into CLI (NCT00392509) also appears to have found success in treating patients with CLI with adult stem cells; Aldagen are now working on treatment for congestive heart failure using stem cell therapy. Active studies include The University of Wisconsin’s research into adult stem cell therapy for severe leg artery disease, including critical limb ischaemia (NCT00913900), which is, at the time of writing, openly recruiting patients, and a Tufts Medical Center study is likely to begin recruitment in the coming months for their stem cell study on CLI (NCT01245335). With so many trials nearing completion and getting underway, it appears that the poor prognosis for those with critical limb ischaemia due to peripheral arterial disease may finally be being addressed through stem cell therapy.
