Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease



Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell‐based therapies in ALS/MND has not been fully evaluated, given the paucity of high‐quality clinical trials. Based on data from preclinical studies, cell‐based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell‐based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs).


To assess the effects of cell‐based therapy for people with ALS/MND, compared with placebo or no treatment.

Search methods

On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies.

Selection criteria

We included RCTs that assigned people with ALS/MND to receive cell‐based therapy versus a placebo or no additional treatment. Co‐interventions were allowed, provided that they were given to each group equally.

Data collection and analysis

We followed standard Cochrane methodology.

Main results

Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow‐mesenchymal stem cells (BM‐MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC‐NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies.

The only study that contributed to the outcome data in the review involved 64 participants, comparing BM‐MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions.

Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) score from baseline to six months after cell injection was slightly reduced (better) in the BM‐MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low‐certainty evidence). ALSFRS‐R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM‐MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD –0.53, 95% CI –5.37 to 4.31; 1 RCT, 56 participants; low‐certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low‐certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low‐certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low‐certainty evidence). The study did not measure muscle strength.

Authors’ conclusions

Currently, there is a lack of high‐certainty evidence to guide practice on the use of cell‐based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low‐certainty evidence that BM‐MSC may slightly reduce functional impairment measured on the ALSFRS‐R after four to six months, this was a small phase II trial that cannot be used to establish efficacy.

We need large, prospective RCTs with long‐term follow‐up to establish the efficacy and safety of cellular therapy and to determine patient‐, disease‐ and cell treatment‐related factors that may influence the outcome of cell‐based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell‐based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

Plain language summary

Cell‐based therapies for amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)

Review question

How effective and safe is cell‐based therapy in people with ALS/MND, when we compare it with an inactive treatment or no treatment?


Amyotrophic lateral sclerosis (ALS; also known as motor neuron disease or MND) is a condition in which nerves in the brain and spinal cord that control movement (motor neurons) stop working. A person with ALS/MND has difficulty moving, swallowing, chewing and speaking, which become worse over time. Half of people with ALS/MND die within three years of their first symptoms. Weakness of muscles used in breathing often leads to death. The condition currently has no cure. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected.

Cell‐based therapy can be defined as injection of cellular material into a person to treat disease. Various types of cell‐based therapies have been tried in ALS/MND, including stem cell therapy. Stem cell therapy aims to provide new motor neurons, which may help stop or slow down disease progression in people with ALS/MND. Previous reviews supported the use of cell‐based therapy as a potential means of delaying the disease course in ALS/MND, but these were mainly based on preclinical animal models. Randomised controlled trials (RCTs) provide the most reliable evidence. In RCTs, one group receives the test treatment, and the other, ‘control’ group has an alternative treatment, a dummy treatment (placebo) or no treatment. Well‐performed RCTs provide the best evidence. Studies with no untreated group for comparison and small clinical trials have found no clinical benefits. Limited data from non‐RCTs involving a small number of people with ALS/MND and a short follow‐up period suggested that cell‐based therapy may slow disease progression. There is currently no approved cell‐based therapy for ALS/MND. We undertook this review to assess the RCT evidence now becoming available.

Study characteristics

Cochrane review authors searched medical databases for clinical trials. They found two completed RCTs that assessed the effects of cell‐based therapy over a six‐month follow‐up period. One study was not fully published and did not provide numerical data. Both studies were funded by stem cell companies. One study, which included 64 people with ALS/MND, provided data. The people taking part in the trial had an average time since symptom onset of about two years. They had mild to moderate problems with motor function (ability to perform physical tasks) at the start of the trial (with an average of 35 on the ALS Functional Rating Scale‐revised, on which a score of 0 indicates greatest impairment and 48 is normal function).

Key results and quality of the evidence

The study provided low‐quality evidence that stem cells obtained from people’s own bone marrow (the cells in the centre of bone) did not result in significant side effects. The cell implantation procedure was well tolerated. Based on evidence from this trial, stem cell treatment may slightly reduce decline in motor function at six months, but may not improve breathing or quality of life at four months, or overall survival at six months. Based on the very limited evidence available, any benefit is uncertain due to there being only one poorly conducted study and results within the study varies. We urgently need large, well‐designed clinical trials to establish whether or not cell‐based therapies have a clear clinical benefit in ALS/MND. Major goals of future research are to identify the right type and amount of cells to use, and how best to administer them.

The evidence is up to date as of July 2019.

Authors’ conclusions

Implications for practice

Limited evidence of very low‐to‐low certainty from a single randomised controlled trial shows that autologous bone marrow‐mesenchymal stem cells treatment may reduce the decline in disability at six months in people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), but the available evidence is not sufficient to enable a clear conclusion regarding the therapeutic efficacy and safety of cell‐based therapy in ALS/MND.

Implications for research

To date, there is no conclusive evidence that cell‐based therapy alters the natural course of ALS/MND and prolongs survival, with currently available evidence limited by imprecision as a result of small sample size. There were significant shortcomings related to the design of the available published studies. We found significant variability between trials with regards to selection criteria, outcome measures, and types of cells and methods of cell implantation. Moreover, these trials were generally underpowered to show any clinical benefit. Prospective RCTs with larger sample size and longer‐term follow‐up are urgently required to assess the clinical benefits of cell‐based therapy including improvement in disease progression and quality of life and prolongation of survival in people with ALS/MND. Importantly, data from well‐designed trials might determine patient‐, disease‐ and cell treatment‐related factors that could potentially influence the clinical outcomes of cell‐based therapy.

Questions remain as to the optimal cell source, phenotype and dose, as well as transplantation method and protocol that would be key elements in designing an optimal cell‐based therapy programme for people with ALS/MND; these should be the major goals of future research.

Combination of cellular therapy with standard therapy (riluzole) or novel neuroprotective agents should also be explored to strengthen the therapeutic efficacy and to find the best possible approach to prevent or reverse the neurological deficit and to prolong survival of this otherwise debilitating and fatal condition.

Studies to investigate the mechanisms of cellular neuroprotection induced by cell implantation would be vital in developing an effective cell‐based targeted therapy in ALS/MND. Future clinical trials should consider the following factors.

  1. Improved trial designs and participant selection criteria, with relevant clinical outcomes.
  2. Long‐term follow‐up to establish long‐term safety and durability of the clinical benefit of cell‐based therapy.
  3. Standardisation of cell products used and cell implantation protocols.
  4. Detailed characterisation of cells used for implantation, including viability and immunophenotype.
  5. In vivo cell tracking using advanced imaging technologies to provide insight into the survival and migratory potential of the grafted cells as well as safety issues such as aberrant differentiation and migration.
  6. Postmortem pathological analysis of brain or spinal cord specimens from people with ALS/MND, to detect evidence of neuroprotection or axonal regeneration of the diseased motor neurons and evidence of aberrant differentiation or tumour formation.
  7. Use of novel cellular sources and treatment approaches (such as induced pluripotent stem cells, cell lines expressing neutrotrophic growth factors and combining mesenchymal stem cell and neural stem cell transplantation).
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