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Stem cell research has been discussed in both the political and popular arenas lately. Some types of stem cell research are controversial; however, not all stem cell research involves harvesting cells from an embryo or an aborted fetus. Another type of stem cell, the adult stem cell, resides within tissues and organs of the body and is responsible for repair after injury. Recent interest has focused on using adult stem cells isolated from a patient's bone marrow to stimulate the development of new blood vessels (a process called angiogenesis) in patients with peripheral vascular disease. These specialized stem cells are referred to as endothelial progenitor cells (EPCs). In laboratory and clinical studies it has been shown that these EPCs are involved in arterial repair and remodeling, as well as angiogenesis. The following case presentation will show how a patient with an ischemic toe ulcer and rest pain, who had no options for conventional revascularization, benefited from the injection of stem cells into her calf muscle. The process of angiogenesis using EPCs will be examined discussing the screening criteria and possible adverse events. The patient's history and progress throughout the recovery period will be reviewed.
This clinical trial has just been registered: Phase II Combination Stem Cell Therapy for the Treatment of Severe Leg Ischemia (MESENDO)
Sponsored by: TCA Cellular Therapy
The purpose of this research study is to compare in patients with double-sided claudication if the transplant of a combination of stem cells obtained from the bone marrow of the same patient will contribute to the formation of new blood vessels in one of the severly diseased ischemic limbs(legs)versus the control limb that receives a placebo product.
Limb Ischemia (LI) is a severe obstruction of the arteries which seriously decrease blood flow to the extremities (mainly feet and legs) and has progressed to the point of severe pain and even skin ulcers or sores.
LI needs conprehensive treatment since the condition will not improve on its own. The overall goal of treatment is to reduce pain and increase blood flow to improve symptoms or save the leg and feet. In many cases, current options for treatment including medications, surgery or endovascular procedures have not been successful.
In the last few years, investigators have explored therapies aimed to increase blood flow to the isschemic vessel by transplanting cells that will promote the development of new vessels in the diseased leg.
The study hypothesis is based on the concept that the process of formation of new blood vessels is complex and requires the participation of several types of stem cells and growth factors. The lack of any of these components will produce vessels which are immature and unable to provide appropriated blood supply to the leg.
Patients eligible to participate in the this study are those suffering from double-sided claudication with poor circulation or severe leg blockages, which are not candidates for surgical procudures.
Once the mixture of stem cells is prepared and the patient's bone marrow is ready, cells will be transplanted into the calf muscle of one the the diseased legs while the other diseased leg will recieve the placebo. Clinical study to evaluate and compare the effacacy of the stem cell transplant will be performed for six months post cell transplant.
Targeting Nonhealing Ulcers of Lower Extremity in Human Through Autologous Bone Marrow-Derived Mesenchymal Stem Cells.
Dash NR, Dash SN, Routray P, Mohapatra S, Mohapatra PC. Rejuvenation Res. 2009 Oct;12(5):359-366.
Bone marrow (BM)-derived mesenchymal stem cells (MSCs) represent a promising population for supporting new concepts in cellular therapy. This study was undertaken to assess the efficacy and feasibility of autologous BM-derived MSCs in the treatment of chronic nonhealing ulcers (diabetic foot ulcers and Buerger disease) of the lower extremities. A total of 24 patients with nonhealing ulcers of the lower limb were enrolled and randomized into implant and control groups. In the implant group, the patients received autologous cultured BM-derived MSCs along with standard wound dressing; the control group received only the standard wound dressing regimen, followed up for at least a 12-week period. Wound size, pain-free walking distance, and biochemical parameters were measured before therapy and at every 2-week interval following intervention. The implant group had significant improvement in pain-free walking distance and reduction in ulcer size as compared to those in the control group. In the implant group for Buerger disease, the ulcer area decreased from 5.04 +/- 0.70 cm(2) to 1.48 +/- 0.56 cm(2) (p < 0.001), whereas the pain-free walking distance increased from 38.33 +/- 17.68 m to 284.44 +/- 212.12 m (p < 0.001). In the diabetic foot ulcer group, the ulcer size decreased from 7.26 +/- 1.41 cm(2) to 2 +/- 0.98 cm(2) (p < 0.001) at 12 weeks. Mononuclear cells were cultured for a minimum of five passages and characterized by cell-surface markers showing CD90(+), CD105(+), and CD34(-). There was no significant alteration in the biochemical parameters observed during the follow-up period, indicating normal liver and renal function following intervention. Biopsy microsection of implanted tissues showed development of dermal cells (mainly fibroblasts), including mature and immature inflammatory cells. The study indicates that autologous implantation of BM-derived MSCs in nonhealing ulcers accelerates the healing process and improves clinical parameters significantly.
Press Release: Final Results from RESTORE-CLI Phase 2b Clinical Trial for Ixmyelocel-T in Treatment of Critical Limb Ischemia Published in the Peer-Reviewed Journal Molecular Therapy
Results Confirm Improvement in Time to Treatment Failure and no Major Safety Issues
Aastrom Biosciences, Inc. ASTM +0.95% , the leading developer of patient-specific expanded multicellular therapies for the treatment of severe chronic cardiovascular diseases, today announced that final results from the company's RESTORE-CLI Phase 2b clinical trial for ixmyelocel-T were published in the peer-reviewed journal Molecular Therapy. The Phase 2b clinical results demonstrated that treatment with ixmyelocel-T improved time to treatment failure in patients with critical limb ischemia (CLI) compared to the control group, and in the subgroup of patients with wounds at baseline demonstrated an improvement in amputation free survival.
The RESTORE-CLI study was a randomized double blind Phase 2b clinical trial comparing the efficacy and safety of ixmyelocel-T to placebo. Patients received a one-time treatment of ixmyelocel-T of 20 intramuscular injections in the treated leg and were followed for 12 months. The results also showed no major safety issues associated with treatment with ixmyelocel-T.
"These results clearly suggest that ixmyelocel-T has the potential to be a promising treatment option in patients with CLI who are not eligible for revascularization. This study represents an important advance in research related to regenerative medicine and the treatment of CLI patients," said Richard J. Powell, M.D., section chief of vascular surgery at the Dartmouth-Hitchcock Medical Center in Lebanon, NH, and a co-principal investigator of the RESTORE-CLI clinical trial.
CLI is the most severe form of peripheral arterial disease (PAD) caused by chronic inflammatory processes associated with atherosclerosis that result in markedly reduced blood flow to the legs, feet and hands. Patients are considered "no option" because they are unable to have revascularization surgery to treat their CLI disease. Major amputation may be necessary for these patients.
In the study, efficacy assessments included time to first occurrence of treatment failure, defined as major amputation, all-cause mortality, doubling of total wound surface area from baseline, or de novo gangrene. A total of 48 patients were treated with ixmyelocel-T and 24 received a placebo. Adverse event rates in both groups were similar. Patients in the treatment arm showed a 62% reduction in risk relative to placebo in the primary efficacy endpoint of time to first occurrence of treatment failure (p =0.0032). A post hoc analysis of the subgroup of 45 patients with wounds at baseline resulted in a 77% risk reduction in time to first occurrence of treatment failure (p=0.0002) and a positive trend in the Phase 3 endpoint of amputation-free survival (61% risk reduction, p=0.0915).
"Based on the results of our RESTORE-CLI study, we recently initiated the Phase 3 REVIVE clinical trial at 80 treatment centers across the U.S. We continue to see very strong promise resulting from our development efforts, and are working aggressively to complete the Phase 3 trial and position ixmyelocel-T for the final phase of regulatory review," said Tim Mayleben, Aastrom president and chief executive officer.
Safety and Effect of Adipose Tissue-Derived Stem Cell Implantation in Patients With Critical Limb Ischemia.
Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS. Circ J. 2012 Apr 12.
Background: Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study.
Methods and Results: The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries.
Conclusions: Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.
Stem cell therapy for critical limb ischemia: what can we learn from cell therapy for chronic wounds?
Caroline Jadlowiec, Robert A Brenes, Xin Li, Wei Lv, Clinton D Protack, Michael J Collins and Alan Dardik Vascular 19 October 2012
Although much progress has been made regarding our knowledge of stem cells and their potential applications for therapeutic angiogenesis, there has been less success with the clinical application of this knowledge to patients with critical limb ischemia (CLI). Patients with CLI often have chronic wounds and newer cell-based therapies for chronic wounds show interesting parallels to stem cell therapy for CLI. Several human-derived wound care products and therapies, including human neonatal fibroblast-derived dermis (Dermagraft®), bilayered bioengineered skin substitute (Apligraf®), recombinant human platelet-derived growth factor and autologous platelet-rich plasma may provide insight into the mechanisms through which differentiated cells can be used as therapy for chronic wounds, and, analogously, by which stem cells might function therapeutically in CLI.
Angiogenesis involves the interplay of endothelial progenitor cells, pericytes, growth factors, and cellular matrix components. The use of mesenchymal stem cells, which are closely related to pericytes and produce diverse angiogenic growth factors and matrix molecules, seems to be a promising therapeutic modality. We postulate that the use of a combination cell product (mesenchymal stem cells in conjunction with a source of endothelial progenitor cells) is safe and efficient and may optimize the clinical results obtained with the use of endothelial progenitor cells alone. This study assessed whether the intramuscular infusion of a combination cell product represents a viable, effective, and lasting therapeutic modality to improve perfusion in severely ischemic limbs.
Patients with limb ischemia (n=26) received an intramuscular (gastrocnemius) infusion of the combination cell product in the most ischemic leg and a placebo product in the (less ischemic) contralateral leg. Clinical follow-up (months 0.5, 1, 2, and 4 postinfusion) included evaluation of pain-free walking time, ankle-brachial index, perfusion scintigraphy, and quality of life survey.
No adverse events occurred after infusion. Efficacy assessment indicated that after cell infusion there was a significant improvement in walking time and ankle-brachial index. In addition, technetium-99m-tetrofosmin scintigraphy demonstrated a significant increase of perfusion in the treated limbs compared with the respective control legs.
This phase II clinical trial shows that the use of a combination cell therapy is safe and effective in increasing blood flow in the ischemic legs of patients with limb ischemia.
Intra-arterial Allogeneic Mesenchymal Stem Cells for Critical Limb Ischemia are Safe and Efficacious: Report of a Phase I Study.
Das AK, Abdullah BJ, Dhillon SS, Vijanari A, Anoop CH, Gupta PK. World J Surg. 2013 Jan 10
Critical limb ischemia (CLI) caused by peripheral arterial disease is associated with significant morbidity and mortality. This condition is associated with a 30 % amputation rate as well as mortality levels which might be as high as 25 %. There is no pharmacological therapy available, but several reports have suggested that mesenchymal stem cells (MSCs) may be a useful therapeutic option.
This study, done at a university hospital, evaluated 13 patients for a phase I trial to investigate the safety and efficacy of intra-arterial MSCs in CLI patients. Eight patients with ten affected limbs were recruited for the study. As two patients (three limbs) died of ischemic cardiac events during the 6-month follow-up period, seven limbs were finally evaluated for the study.
There was significant pain relief. Visual analog scale (VAS) scores decreased from 2.29 ± 0.29 to 0.5 ± 0.34 (p < 0.05), ankle brachial pressure index (ABPI) increased significantly from 0.56 ± 0.02 to 0.67 ± 0.021 (p < 0.01), and transcutaneous oxygen pressure (TcPO(2)) also increased significantly in the foot from 13.57 ± 3.63 to 38 ± 3.47. Similar improvement was seen in the leg as well as the thigh. There was 86 % limb salvage and six of seven ulcers showed complete or partial healing.
It was concluded that intra-arterial MSCs could be safely administered to patients with CLI and was associated with significant therapeutic benefits.