[ARTICLE] Cell-Based Therapies for Stroke: Are We There Yet? – Full Text

Stroke is the second leading cause of death and physical disability, with a global lifetime incidence rate of 1 in 6. Currently, the only FDA approved treatment for ischemic stroke is the administration of tissue plasminogen activator (tPA). Stem cell clinical trials for stroke have been underway for close to two decades, with data suggesting that cell therapies are safe, feasible, and potentially efficacious. However, clinical trials for stroke account for <1% of all stem cell trials. Nevertheless, the resources devoted to clinical research to identify new treatments for stroke is still significant (53–64 million US$, Phase 1–4). Notably, a quarter of cell therapy clinical trials for stroke have been withdrawn (15.2%) or terminated (6.8%) to date. This review discusses the bottlenecks in delivering a successful cell therapy for stroke, and the cost-to-benefit ratio necessary to justify these expensive trials. Further, this review will critically assess the currently available data from completed stroke trials, the importance of standardization in outcome reporting, and the role of industry-led research in the development of cell therapies for stroke.

Introduction

Background

Stroke has a devastating effect on the society worldwide. In addition to its significant mortality rate of 50% as reported in 5-year survival studies (1), it affects as many as 1 in 6 people in their lifetimes, and is the leading cause of disability worldwide (2). A stroke results in a complex interplay of inflammation and repair with effects on neural, vascular, and connective tissue in and around the affected areas of the brain (3). Therefore, sequelae of stroke such as paralysis, chronic pain, and seizures can persist long term and prevent the patient from fully reintegrating into society. Stroke therefore remains the costliest healthcare burden as a whole (4). In 2012, the total cost of stroke in Australia was estimated to be about $5 billion with direct health care costs attributing to $881 million of the total (5).

Unfortunately, treatment options for stroke are still greatly limited. Intravenous recombinant tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT) are currently the only effective treatments available for acute stroke. However, there is only a brief window of opportunity where they can be successfully applied. EVT is performed until up to 24 h of stroke onset (6), while tPA is applied within 4.5 h of stroke onset. Notably, the recent WAKE-UP (NCT01525290) (7) and EXTEND (NCT01580839) trials have shown that this therapeutic window can be safely extended to 9 h from stroke onset. Furthermore, advancements in acute stroke care and neurorehabilitation have shown to be effective in improving neurological function (8). However, there are no treatments that offer restoration of function and as a result, many patients are left with residual deficits following a stroke. Cell-based therapies have shown promising results in animal models addressing the recovery phase following stroke (9). This is encouraging as currently, there are no approved treatment options addressing the reversal of neurological damages once a stroke has occurred (10).

The majority of data from animal studies and clinical trials demonstrate the therapeutic potential of stem cells in the restoration of central nervous system (CNS) function (1112), applicable to neurodegenerative diseases as well as traumatic brain injury. Transplanted stem cells were reportedly able to differentiate into neurons and glial cells, whilst supporting neural reconstruction and angiogenesis in the ischemic region of the brain (13). Previous work demonstrated the ability of mesenchymal stem cells (MSCs) to differentiate into neurons, astrocytes (14), endothelial cells (1516), and oligodendrocyte lineage cells (17) such as NG2-positive cells (18in vitro, and undergo neuronal or glial differentiation in vivo (19). Bone marrow-derived mesenchymal stem cells (BMSCs) have shown potential to differentiate into endothelial cells in vitro (20). Additionally, both BMSCs and adipose stem cells (ASCs) have been shown to demonstrate neural lineage differentiation potential in vitro (2123). Furthermore, stem cells are able to modulate multiple cell signaling pathways involved in endogenous neurogenesis, angiogenesis, immune modulation and neural plasticity, sometimes in addition to cell replacement (3). The delivery of stem cells from the brain, bone marrow, umbilical cord, and adipose tissue, have been reported to reduce infarct size and improve functional outcomes regardless of tissue source (9). While these were initially exciting reports, they raise the question as to the validity of the findings to date since these preclinical reports are almost uniformly positive. The absence of scientific skepticism and robust debate may in fact have negated progress in this field.

Cell-based therapies have been investigated as a clinical option since the 1990s. The first pilot stroke studies in 2005 investigated the safety of intracranial delivery of stem cells (including porcine neural stem cells) to patients with chronic basal ganglia infarcts or subcortical motor strokes (2425). However, since the publication of these reports, hundreds of preclinical studies have shown that a variety of cell types including those derived from non-neural tissues can enhance structural and functional recovery in stroke. Cell therapy trials, mainly targeted at small cohorts of patients with chronic stroke, completed in the 2000s, showed satisfactory safety profiles and suggestions of efficacy (10). Current treatments such as tPA and EVT only have a narrow therapeutic window, limited efficacy in severe stroke and may be accompanied by severe side effects. Specifically, the side effects of EVT include intracranial hemorrhage, vessel dissection, emboli to new vascular territories, and vasospasm (26). The benefit of tPA for patients with a severe stroke with a large artery occlusion can vary significantly (27). This is mainly due to the failure (<30%) of early recanalisation of the occlusion. Thus, despite the treatment options stroke is still a major cause of mortality and morbidity, and there is need for new and improved therapies.

Stem cells have been postulated to significantly extend the period of intervention and target subacute as well as the chronic phase of stroke. Numerous neurological disorders such as Parkinson’s disease (1228), Alzheimer’s disease (29), age-related macular degeneration (30), traumatic brain injury (31), and malignant gliomas (32) have been investigated for the applicability of stem cell therapy. These studies have partly influenced the investigation of stem cell therapies for stroke. A small fraction of stem cell research has been successfully translated to clinical trials. As detailed in Table 1, most currently active trials use neuronal stem cells (NSCs), MSCs or BMSCs (3537), including conditionally immortalized neural stem-cell line (CTX-DP) CTX0E03 (38), neural stem/progenitor cells (NSCs/NPSCs) (e.g., NCT03296618), umbilical cord blood (CoBis2, NCT03004976), adipose (NCT02813512), or amnion epithelial cells (hAECs, ACTRN 1261800076279) (39).

Table 1. Challenges and bottlenecks of stem cell therapy and clinical trials using stem cells (3334).

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Continue —>  Frontiers | Cell-Based Therapies for Stroke: Are We There Yet? | Neurology

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