Stem cell (SC) therapy has been proposed as a promising treatment option for ALS based on the potential effects on various pathogenic mechanisms through trophic and/or immunomodulatory support and, perhaps, by providing host neural cell replacement9. Indeed, in the past two decades, transplantation of various SC products has been evaluated in numerous Phase I and II clinical trials designed to assess feasibility and safety, but also looking for indications of clinical benefit, reflected by changes in the progression rate of the ALS functional ratings score (ALSFRS) and the respiratory function (forced or slow vital capacity, F/SVC). Regarding efficacy, results are mostly inconclusive due to the limited sample size of the trials and the heterogeneity of individual progression. In addition, very few trials are controlled, as inclusion of adequate sham controls for invasive procedures is problematic and often unethical. Therefore, we decided to conduct a meta-analysis of SC trials considering all clinical trials that report the evolution of each patient before and after cell administration. In this way, we aimed to determine the efficacy of the SC administration despite individual heterogeneity.
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SC therapy is viewed as a promising option for ALS because these cells potentially target several of the putative pathogenic mechanisms involved in the onset and progression of the disease, although explicit target engagement for each cell product needs further validation9. Here, we designed a meta-analysis to examine individual progression as a measure of efficacy, using the ALSFRS-R change, which is considered to be linear for the majority of the illness24 Overall, and with the limitations that are discussed below, we found that, based on current evidence, cell therapy has a transient positive effect on the progression of the disease, as measured by the ALSFRS-R. In the available controlled studies that we reviewed (76 patients receiving MSCs or MNCs), there was also a trend for a better progression in patients receiving cell therapy. In those studies, the administration of MSCs was intrathecal17 or intrathecal + intramuscular25, and intracortical for MNCs26.
Initially driven to achieve neuronal cell replacement, fetal NSCs were embraced as a cell source that is renewable while being inherently non-tumorigenic and with low immunogenicity37. Nonetheless, NSCs appear more likely to differentiate into glial cells (astrocytes and oligodendrocytes) and to provide trophic support to dying motoneurons35. A toxic effect of astrocytes has been well established in ALS spinal cord, therefore, providing healthy glia into the area may have a positive impact on disease outcome. The fetal NSCs used in these studies had different origins in the spinal cord (Neuralstem Inc.)20,21 or forebrain22 which may define their restorative capacity, as regional differences in glial cells are becoming increasingly recognized38. Immunosuppression is also a factor that needs to be considered when using allogeneic cells, even if fetal NSCs appear to induce little immunogenicity39 and survival has been documented after withdrawal of immunosuppression40. In that postmortem analysis, nests of transplanted spinal NSCs were identified but did not show significant differentiation into glia and only subsets were labeled for SOX2 or NeuN (a marker of mature neurons)40. Indeed, protective mechanisms may be mediated by the NSCs or by other cell types as Blanquer et al. reported the presence of nests of MNC transplanted cells surrounding motoneurons which showed less ubiquitin inclusions and were more numerous at targeted levels (if only 25% from control)23. With currently available datasets, these three SC types can only be compared in intraspinal administration, but the observed effects are too small to draw any conclusion.
Overall, based on current evidence, we can conclude that SC therapy may have a positive, if transient, effect on ALS progression, but not on the pulmonary function, and that both the cell product and the delivery route need to be carefully reconsidered and optimized in adequately controlled preclinical models before moving forward in ALS patients. Furthermore, for a SC therapy to be successful, a third factor, the recipient, needs also to be integrated in the equation. Illustrating this point, the results of NurOwn Phase III trial (NCT03280056) in which patients received three intrathecal injections of autologous pre-conditioned BM-MSCs or placebo were released last month. The trial did not meet the endpoint but analysis of a subgroup of early patients showed the anticipated difference between treated and placebo groups. The company has announced initiation of expanded access program (compassionate use) for some patients who completed the clinical trial and meet specific eligibility criteria ( -cell.com/2020-11-17-BrainStorm-Announces-Topline-Results-from-NurOwn-R-Phase-3-ALS-Study). Thus, a better understanding of disease mechanisms in individual patients would greatly enhance the possibility to implement the most suitable SC strategy to modify the prognosis of ALS patients.
In this review, we describe the general information of MSCs, mechanisms of MSC therapies (i.e., the conducting effect of MSCs), recently published outcomes of MSC therapy, clinical trials that have recently started or will begin soon, and recent research trends using extracellular vesicles obtained from MSCs.
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