Are Cell-Based Therapies Safe and Effective in the Treatment of Neurodegenerative Diseases? A Systematic Review with Meta-Analysis

Abstract

Over the past two decades, significant advances have been made in the field of regenerative medicine. However, despite being of the utmost clinical urgency, there remains a paucity of therapeutic strategies for conditions with substantial neurodegeneration such as (progressive) multiple sclerosis (MS), spinal cord injury (SCI), Parkinson’s disease (PD) and Alzheimer’s disease (AD). Different cell types, such as mesenchymal stromal cells (MSC), neuronal stem cells (NSC), olfactory ensheathing cells (OEC), neurons and a variety of others, already demonstrated safety and regenerative or neuroprotective properties in the central nervous system during the preclinical phase. As a result of these promising findings, in recent years, these necessary types of cell therapies have been intensively tested in clinical trials to establish whether these results could be confirmed in patients. However, extensive research is still needed regarding elucidating the exact mechanism of action, possible immune rejection, functionality and survival of the administered cells, dose, frequency and administration route. To summarize the current state of knowledge, we conducted a systematic review with meta-analysis. A total of 27,043 records were reviewed by two independent assessors and 71 records were included in the final quantitative analysis. These results show that the overall frequency of serious adverse events was low: 0.03 (95% CI: 0.01–0.08). In addition, several trials in MS and SCI reported efficacy data, demonstrating some promising results on clinical outcomes. All randomized controlled studies were at a low risk of bias due to appropriate blinding of the treatment, including assessors and patients. In conclusion, cell-based therapies in neurodegenerative disease are safe and feasible while showing promising clinical improvements. Nevertheless, given their high heterogeneity, the results require a cautious approach. We advocate for the harmonization of study protocols of trials investigating cell-based therapies in neurodegenerative diseases, adverse event reporting and investigation of clinical outcomes.

A review of stem cell therapy: An emerging treatment for dementia in Alzheimer's and Parkinson's disease

“…α‐synuclein aggregates are known to be toxic to cells, leading to neuronal deaths in many α‐synucleinopathies (Hirschi et al., 2003 ). Neuronal cells release α‐synuclein aggregates by the process of exocytosis (Hirschi et al., 2003 ), which are then taken up via endocytosis by neurons and glial cells (Van den Bos et al., 2022 , Salem et al., 2014 , Mo et al., 2012 ). Furthermore, it is suggested that the interaction between α‐synuclein and N‐methyl‐D‐aspartate (NMDA) receptors could facilitate clathrin‐mediated endocytosis of NMDA receptors (Gomperts, 2016 ).…”

Safety and Efficacy of Cell Transplantation on Improving Motor Symptoms in Patients With Parkinson’s Disease: A Meta-Analysis

“…Even among studies for the same disease and using the same cell type, there is large variability between these parameters. all results should be interpreted with caution (Grekhnev et al, 2022;Van-den-Bos et al, 2022). In terms of cell type selection: Transplanted cells should meet criteria regarding safety, efficacy, stability, reproducibility, and scalability before transplantation into patients.…”

Therapy with mesenchymal stem cell transplantation in multiple sclerosis is ready for prime time: No

“…In conclusion, despite 15 years since the first pilot trial with MSC in MS published, 9 only a very limited number of small studies have been reported, 6 providing only some preliminary information about treatment efficacy. The unfortunate results from the MESEMS clinical trial should be carefully considered, given that it enrolled the greatest number of patients of any study conducted thus far, along with the rigorous standardization procedure applied to the study, the cell manufacturing, and the statistical design.…”

“…On the 'NO' side, Drs. Uccelli and Freedman mostly focus on the results of MESEMS, the largest investigator-initiated, randomised, double-blind, placebo-compared phase II study of MSCs in MS. 6 MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) concluded that a single IV dose of autologous MSCs has no effect on MS disease activity, de facto providing a final answer to whether MSCs Visit SAGE journals online journals.sagepub.com/ home/msj SAGE journals…”

“…Several small human clinical trials ensued and concluded universally that MSC administration to MS patients, regardless the route of administration, was safe and feasible and reported some effect on Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) metrics and might even reverse long-standing visual deficits. 5 Despite these optimistic “hints,” the interpretation of results concerning efficacy of MSC on clinical and radiological parameters is, however, controversial: 6 studies were vastly underpowered to generate consistent information on treatment effectiveness due to the limited number of patients and the heterogeneity of MS subtypes; furthermore, they were uncontrolled and unblinded, short-duration studies with limited extension of the clinical and radiological follow-up, rendering most results somewhat anecdotal, particularly for progressive MS patients. Other as yet unresolved issues make it difficult to compare results from these small studies, including the different sources for MSC isolation (e.g.…”