Rise of Cell Therapy Trials for Stroke: Review of Published and Registered Studies

Stroke is the second leading cause of death and the third leading cause of disability worldwide. Approximately 16 million first-ever strokes occur each year, leading to nearly 6 million deaths. Nevertheless, currently, very few therapeutic options are available. Cell therapies have been applied successfully in different hematological diseases, and are currently being investigated for treating ischemic heart disease, with promising results. Recent preclinical studies have indicated that cell therapies may provide structural and functional benefits after stroke. However, the effects of these treatments are not yet fully understood and are the subject of continuing investigation. Meanwhile, different clinical trials for stroke, the majority of them small, nonrandomized, and uncontrolled, have been reported, and their results indicate that cell therapy seems safe and feasible in these conditions. In the last 2 years, the number of published and registered trials has dramatically increased. Here, we review the main findings available in the field, with emphasis on the clinical results. Moreover, we address some of the questions that have been raised to date, to improve future studies.

There were31 articles in the English language involving 20 different trials of cell therapies for stroke, with a total of 243 treated patients. Sixteen of these articles and 12 of the trials were published in the last 2 years. Twelve trials were for ischemic, two for hemorrhagic, and six for ischemic or hemorrhagic strokes. Six trials performed intravenous transplants; five injected the cells in the parenchyma; five used the intra-arterial route; three carried out intrathecal administrations; and one trial compared intra-arterial and intravenous routes.

Schematic illustrating the different cells and routes of administration used in published trials. The schematic also illustrates other types of cells used in registered trials (in dotted rectangles). NT2N, human teratocarcinoma-derived neurons; UC-MSCs, umbilical cord-derived mesenchymal stem cells; UCB-MNCs, umbilical cord blood-mononuclear cells; BM-MNCs, bone marrow-mononuclear cells; BM-MSCs, bone marrow-mesenchymal stem cells; PB-HSPC, peripheral blood-hematopoietic stem/progenitor cell; NSPCs, neural stem/progenitor cells; OECs, olfactory-ensheathing cells; MSCs, mesenchymal stem cells; EPCs, endothelial progenitor cells.

Stroke is responsible for 11.1% of all deaths, and is the second leading cause of death worldwide after ischemic heart disease. After a stroke, roughly a quarter of patients die within a month, and half within 1 year. There were an estimated 16 million first-ever strokes and 5.7 million deaths in 2005. These numbers are expected to increase to 23 million first-ever strokes and 7.8 million deaths in 2030. Stroke was responsible for 102 million disability-adjusted life years (DALYs) in 2010, an increase to the third leading cause of DALYS from the fifth leading cause in 1990. Approximately 80% of all strokes are ischemic, and currently, tissue plasminogen activator (tPA) is the only pharmacological agent approved for treatment of acute ischemic stroke. However, tPA therapy has important limitations, notably the narrow therapeutic window of 4.5 h, which limits its use to a small minority (2% to 4%) of patients.

Several preclinical studies have indicated that there is a structural and/or functional recovery after intracerebral, intra-arterial, and intravenous therapy with different cell types [8,103]. In clinical studies, most of the available data come from bone marrow cell therapies for malignant and nonmalignant diseases. A meta-analysis of 50 clinical trials using cell therapies for acute and chronic ischemic heart disease with a total of 2625 patients has found that bone marrow cell treatment improves left ventricle (LV) ejection fraction, infarct size, LV end-diastolic volume, and LV end-systolic volume. A recent trial investigating the transendocardial injection of autologous or allogeneic BM-MSCs in 30 patients with ischemic cardiomyopathy improved ventricular remodeling, functional capacity, and quality of life, with a 13-month follow-up. For peripheral artery disease, a meta-analysis of 37 trials involving injection of bone marrow cells, peripheral blood cells, or G-CSF indicated that cell therapies, but not G-CSF, significantly improved the indices of ischemia such as the ankle–brachial index, transcutaneous oxygen tension, pain-free walking distance, and also hard endpoints such as ulcer healing and amputation.

Although clinical results with other ischemic diseases and preclinical studies for stroke are encouraging, there are still many questions regarding the possible mechanisms of action of the cells and the optimal treatment protocol. One of the main questions to be answered is related to the best cell type to be used in these patients. A recent meta-analysis of 117 preclinical stroke studies indicated that for structural effects, autologous stem cells were more effective than allogeneic cells, while for functional effects, allogeneic cells were more effective. Interestingly, the authors found no difference between the embryonic and adult allogeneic cells for either structural or functional outcomes. This would support the use of adult cells rather than embryonic or fetal-derived cells; the former are preferred because of the ethics concerns associated with the latter. Moreover, bone marrow cells can be harvested from the patient for autologous therapy, avoiding the necessity for immunosuppressants

The results from preclinical studies have indicated that cell therapies can lead to the structural and functional benefits after a stroke. However, there is still a need to examine the ideal subset of stem cells to be used. Further, aspects such as the mechanisms for such improvements and the optimal treament protocol are not yet fully understood and require further evaluation. Nevertheless, different clinical studies, the majority of them small, nonrandomized and uncontrolled, have now been reported and indicate that cell therapy seems safe, feasible, and potentially efficacious. The increasing number of ongoing studies, including large randomized double-blind studies, have the potential to determine the efficacy of cell therapy for stroke and to translate the preclinical findings into clinical practice.

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