Treatment of peripheral arterial disease using stem and progenitor cell therapy

Abstract

Peripheral arterial disease (PAD) is a highly prevalent atherosclerotic syndrome associated with significant morbidity and mortality. PAD is most commonly caused by atherosclerosis obliterans (ASO) and thromboangiitis obliterans (TAO), and can lead to claudication and critical limb ischemia (CLI), often resulting in a need for major amputation and subsequent death. Standard treatment for such severe cases of PAD is surgical or endovascular revascularization. However, up to 30% of patients are not candidates for such interventions, due to high operative risk or unfavorable vascular involvement. Therefore, new strategies are needed to offer these patients a viable therapeutic option. Bone-marrow derived stem and progenitor cells have been identified as a potential new therapeutic option to induce angiogenesis. These findings prompted clinical researchers to explore the feasibility of cell therapies in patients with peripheral and coronary artery disease in several small trials. Clinical benefits were reported from these trials including improvement of ankle-brachial index (ABI), transcutaneous partial pressure of oxygen (TcO(2)), reduction of pain, and decreased need for amputation. Nonetheless, large randomized, placebo-controlled, double-blind studies are necessary and currently ongoing to provide stronger safety and efficacy data on cell therapy. Current literature is supportive of intramuscular bone marrow cell administration as a relatively safe, feasible, and possibly effective therapy for patients with PAD who are not subjects for conventional revascularization.

Autophagy - the friendly fire in endothelial cell regeneration. Focus on “Autophagy in endothelial progenitor cells is cytoprotective in hypoxic conditions”

“…patients with ischemic disorders such as peripheral artery disease or in individuals having a recent, acute ischemic event such as myocardial infarction (1,5). However, high rates of cell death and ineffective cell engraftment have plagued these otherwise promising transplantation trials (3).…”

Cell Therapy of Critical Limb Ischemia (Problems and Prospects)

“…Это касается применения мононуклеарной фракции клеток аутологичного кост-ного мозга или периферической крови [98] и высоко-очищенных фракций эндотелиальных клеток-предше-ственников (CD133 + клетки) и CD34 + гемопоэтических СК [99,100]. Терапия заболеваний периферических ар-терий мононуклерными фракциями клеток костного мозга или периферической крови (после мобилизации Г-КСФ) оказалась более успешной, чем использование вышеупомянутых высокоочищенных гемопоэтических СК [100].…”

“…Однако они выполнены на небольшом числе пациентов и не позволяют сделать обоснованное заключение. Важно иметь в виду, что пациенты, нуждающиеся в терапевти-ческой неоваскуляризации, часто имеют сопутствующие кардиоваскулярные факторы риска, и применение у них клеточной терапии может сопровождаться негативны-ми реакциями, такими как кровотечения или тромбо-образование [98]. Клеточная терапия у таких больных может не оказать ожидаемого положительного эффекта вследствие снижения числа СК или их регенераторного потенциала [106][107][108].…”

Development of a thermoresponsive chitosan gel combined with human mesenchymal stem cells and desferrioxamine as a multimodal pro-angiogenic therapeutic for the treatment of critical limb ischaemia

“…Symptoms of CLI include pain at rest, ulceration and gangrene. Amputation of the affected limb is necessary in approximately 30% of cases and prognosis following amputation is bleak, with a mere 30% survival rate within five years [1][2]. Treatment often requires invasive revascularisation procedures, which are not suitable for a significant percentage of patients.…”

“…To date, clinical trials investigating the safety and efficacy of pro-angiogenic therapy in PAD patients including gene, growth factor or cell-based therapies have found that treatments were generally well tolerated but that efficacy was modest or inconsistent, a fact which has been partially attributed to incomplete knowledge of appropriate doses, duration of dosage and delivery methods. Current strategies have not yet resulted in satisfactory clinical efficacy and the use of single pro-angiogenic agents does not appear sufficient to adequately drive the complex vascularisation process in humans [1,[4][5]. The co-delivery of more than one agent has been shown to produce synergistic increases in pro-angiogenic efficacy in pre-clinical models of CLI [6][7].…”