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Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

ABSTRACT: BACKGROUND:Published studies seeking to improve survival in amyotrophic lateral sclerosis (ALS) have poor results in humans, although there are several studies in animal models with positive results. METHODS:We conducted a systematic review and meta-analysis of studies that were published between March 2009 and March 2015 on stem cell therapy and survival in animal models and patients with ALS. A total of 714 articles were identified, and from these, we selected preclinical in vivo studies and retrospective clinical studies. RESULTS AND CONCLUSIONS:A meta-analysis confirmed the efficacy of stem cell therapy in improving survival in preclinical trials, where a mean difference of 9.79 days (95% confidence interval: 4.45 - 15.14) in lifespan favored stem cell therapy. In contrast, the number of clinical studies is still insufficient to assess their effectiveness, and these studies only demonstrate the absence of serious adverse events. However, even this conclusion should be interpreted with caution because clinical studies are retrospective and heterogeneous and have an unsatisfactory quality.

SUBMITTER: Moura MC

PROVIDER: S-EPMC4780495 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

Moura Mirian Conceicao MC Novaes Maria Rita Carvalho Garbi MR Zago Yuri S S P YS Eduardo Emanoel Junio EJ Casulari Luiz Augusto LA

Journal of clinical medicine research 20160227 4

<h4>Background</h4>Published studies seeking to improve survival in amyotrophic lateral sclerosis (ALS) have poor results in humans, although there are several studies in animal models with positive results.<h4>Methods</h4>We conducted a systematic review and meta-analysis of studies that were published between March 2009 and March 2015 on stem cell therapy and survival in animal models and patients with ALS. A total of 714 articles were identified, and from these, we selected preclinical in viv ...[more]

PMID: 26985252

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Project description:Interventions targeting mitochondrial dysfunction have the potential to extend survival in preclinical models of amyotrophic lateral sclerosis. The aim of this systematic review was to assess the efficacy of targeting mitochondria as a potential therapeutic target in amyotrophic lateral sclerosis. Preclinical studies written in the English language were identified with no restrictions on publication date from PubMed, Medline and EMBASE databases. All studies adopting interventions targeting mitochondria to treat amyotrophic lateral sclerosis in genetic or drug-induced organism models were considered for inclusion. A total of 76 studies were included in the analysis. Survival data were extracted, and the meta-analysis was completed in RevMan 5 software. We show that targeting mitochondrial dysfunction in amyotrophic lateral sclerosis results in a statistically significant improvement in survival (Z = 5.31; P<0.00001). The timing of administration of the intervention appears to affect the improvement in survival, with the greatest benefit occurring for interventions given prior to disease onset. Interventions at other time points were not significant, although this is likely to be secondary to a lack of publications examining these timepoints. The quality score had no impact on efficacy, and publication bias revealed an overestimation of the effect size, owing to one outlier study; excluding this led to the recalculated effect size changing from 5.31 to 3.31 (P<0.00001). The extant preclinical literature indicates that targeting mitochondrial dysfunction may prolong survival in amyotrophic lateral sclerosis, particularly if the intervention is administered early. A limitation of current research is a significant bias towards models based on superoxide dismutase 1, with uncertainty about generalisability to amyotrophic lateral sclerosis with an underlying TAR DNA binding protein 43 proteinopathy. However, further mechanistic research is clearly warranted in this field.

Project description:BackgroundMutation in the ubiquitously expressed cytoplasmic superoxide dismutase (SOD1) causes an inherited form of Amyotrophic Lateral Sclerosis (ALS). Mutant synthesis in motor neurons drives disease onset and early disease progression. Previous experimental studies have shown that spinal grafting of human fetal spinal neural stem cells (hNSCs) into the lumbar spinal cord of SOD1(G93A) rats leads to a moderate therapeutical effect as evidenced by local ?-motoneuron sparing and extension of lifespan. The aim of the present study was to analyze the degree of therapeutical effect of hNSCs once grafted into the lumbar spinal ventral horn in presymptomatic immunosuppressed SOD1(G93A) rats and to assess the presence and functional integrity of the descending motor system in symptomatic SOD1(G93A) animals.Methods/principal findingsPresymptomatic SOD1(G93A) rats (60-65 days old) received spinal lumbar injections of hNSCs. After cell grafting, disease onset, disease progression and lifespan were analyzed. In separate symptomatic SOD1(G93A) rats, the presence and functional conductivity of descending motor tracts (corticospinal and rubrospinal) was analyzed by spinal surface recording electrodes after electrical stimulation of the motor cortex. Silver impregnation of lumbar spinal cord sections and descending motor axon counting in plastic spinal cord sections were used to validate morphologically the integrity of descending motor tracts. Grafting of hNSCs into the lumbar spinal cord of SOD1(G93A) rats protected ?-motoneurons in the vicinity of grafted cells, provided transient functional improvement, but offered no protection to ?-motoneuron pools distant from grafted lumbar segments. Analysis of motor-evoked potentials recorded from the thoracic spinal cord of symptomatic SOD1(G93A) rats showed a near complete loss of descending motor tract conduction, corresponding to a significant (50-65%) loss of large caliber descending motor axons.Conclusions/significanceThese data demonstrate that in order to achieve a more clinically-adequate treatment, cell-replacement/gene therapy strategies will likely require both spinal and supraspinal targets.

Dataset Information

Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

Publications

Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis.

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