Medical need

Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and death from cardiovascular complications. In addition to symptomatic therapy, the gold-standard treatment of severe PAD and CLI is surgical or endovascular revascularization.
Meta-analysis did not reveal any significant difference in long-term outcome between the two methods of revascularization. However, up to 30% of patients are not candidate for such interventions, due to excessive operative risk or unfavorable vascular involvement.
Therapies targeting only revascularization and/or nascent collateral vessel formation by supporting vascularization have proven ineffective to date and indicate that the ischemic muscle tissue is not dispensable and therefore a “restoration of flow approach” is not independently sufficient to rescue the limb. Myopathy and vasculopathy are interrelated components of a coordinated tissue response to CLI.

In summary, current clinical interventions are largely ineffective and therapeutic angiogenesis-based trials have shown limited if any efficacy, highlighting the need for new ideas and novel therapeutic approaches.

The application of gene- and cell-based Advanced Therapy Medicinal Products (ATMP) to promote angiogenesis has been proposed as a novel concept to treat lower-limb CLI, particularly for patients with no options for revascularization. The table II summarizes some of the numerous ongoing or very recently finished studies on cell therapy in CLI.


Table II. Overview on recent clinical trials using BM-stem/progenitor cells for treatment of critical limb ischemia

Currently, the largest scale combination cell study reported is the RESTORE-CLI trial, which has recently completed phase II in patients with CLI.
In a more recent meta-analysis of 10 studies, totaling 499 patients, which fulfilled the quality criteria (randomised, controlled etc.), no significant differences were observed in major amputation rates (relative risk [RR] 0.91), survival (RR 1.00), and amputation-free-survival (RR 1.03) between the BM MNC/enriched progenitor cell-treated and placebo-treated patients. The meta-analysis concluded limited advantage of bone marrow-derived cell therapy on the primary outcome measures in patients with CLI.

Interest is further growing regarding the benefits of specific cells types ranging from surface marker enriched BM-MNC progenitor cells (CD34+, CD133+), endothelial progenitor cells (EPCS), and MSC from different sources, and combinations thereof. Early results of some phase I trials were promising, as patients injected with MSCs demonstrated improved walking time, ankle-brachial indices (ABI), and limb perfusion. Follow-up Phase II studies evaluated the efficacy of intramuscular injections of a combination product of BM-MNCs and BM-MSCs and regardless of dosage, injected patients showed significant improvements.


T.E. Ryan, C.A. Schmidt, T. D. Green, D.A. Brown, P. D. Neufer, J. M. McClung. 2015. Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia. Front Physiol. 2015; 6: 336. Published online 2015 Nov 18.  doi:  10.3389/fphys.2015.00336

R.J. Powell, W.A. Marston,, S.A. Berceli, R.H. Guzman, A.T. Longcore et al. 2012. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Molecular Therapy, 20(6), 1280–1286.

J. Yan, G. Tie, T. Yu Xu, K. Cecchini, L.M. Messina. 2013. Mesenchymal Stem Cells as a Treatment for Peripheral Arterial Disease: Current Status and Potential Impact of Type II Diabetes on Their Therapeutic Efficacy. Stem Cell Rev and Rep. 9:360–372.


Project objectives