A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia

Abstract

BackgroundPeripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI). Bone marrow derived Mesenchymal Stem Cells (BM- MSCs) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ. The primary objective was to determine the safety of BM- MSCs in patients with CLI.MethodsProspective, double blind randomized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment. The primary end point was incidence of treatment – related adverse events (AE). Exploratory efficacy end points were improvement in rest pain, increase in Ankle Brachial Pressure Index (ABPI), ankle pressure, healing of ulcers, and amputation rates. Twenty patients (BM-MSC: Placebo = 1:1) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo (PlasmaLyte A) at the gastrocnemius muscle of the ischemic limb.ResultsImprovement was observed in the rest pain scores in both the arms. Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group. Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events (SAE) were similar in both the arms (5 in BM-MSC and 4 in the placebo group). SAEs resulted in death, infected gangrene, amputations in these patients. It was observed that the SAEs were related to disease progression and not related to stem cells.ConclusionBM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight. Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies.Trial registrationNIH website (http://www.clinicaltrials.gov/ct2/show/NCT00883870)

Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy

“…These analyses revealed similar results in both groups, suggesting that the administered allogeneic cells did not adversely alter the immunological and lymphocytic profile [13]. …”

Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis

“…Their plasticity, immunosuppressive potential, immuno-modulatory properties [18,19], and trophic activity [20,21] make MSCs critical players in tissue homeostasis. For these reasons, MSCs are considered a suitable tool for regenerative medicine and have been already introduced in a number of clinical trials for tissue repair [18,[22][23][24][25]. Although they share similar epitope profiles, MSCs derived from different tissues show significant differences in the differentiation, proliferation, and migration potential, which depend on the tissue they originate from as they receive inputs that directly affect their specification [2,26,27].…”

Adult stem cells in neural repair: Current options, limitations and perspectives

“…MSCs also showed great results when transplanted with T cells, controlling inflammatory activity in order to create the proper microenvironment for cell transplantation [24] . The immunomodulating effect of MSCs has also been reported in other clinical trials and MSCs have been shown to play an important role as immunomodulators and angiogenic agents in drug resistant patients as well as in patients with cerebral palsy, critical limb ischemia and kidney transplants [25][26][27][28][29][30][31][32] . In another study conducted with 40 patients, bone regeneration was achieved when a great number of CD34 + cells were transplanted to the lesion site, 20 patients achieved mature bone regeneration, even in the group that received a low number of cells 4 patients achieved bone regeneration.…”