Abdul Wahid 2019

Cochrane
Library
Cochrane Database of Systematic Reviews

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron
disease (Review)
Abdul Wahid SF, Law ZK, Ismail NA, Lai NM
Abdul Wahid SF, Law ZK, Ismail NA, Lai NM.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.
Cochrane Database of Systematic Reviews 2019, Issue 12. Art. No.: CD011742.
DOI: 10.1002/14651858.CD011742.pub3.
www.cochranelibrary.com

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 6
OBJECTIVES.................................................................................................................................................................................................. 7
METHODS..................................................................................................................................................................................................... 7
RESULTS........................................................................................................................................................................................................ 10
Figure 1.................................................................................................................................................................................................. 11
Figure 2.................................................................................................................................................................................................. 13
DISCUSSION.................................................................................................................................................................................................. 15
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 16
ACKNOWLEDGEMENTS................................................................................................................................................................................ 17
REFERENCES................................................................................................................................................................................................ 18
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 24
DATA AND ANALYSES.................................................................................................................................................................................... 32
Analysis 1.1. Comparison 1 Autologous bone marrow-mesenchymal stem cells (BM-MSC) versus no treatment, Outcome 1 33
Functional impairment: change in Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised score..................................
Respiratory function: change in % forced vital capacity....................................................................................................................
Quality of life: change in 36-item Short Form score...........................................................................................................................
Survival at 6 months.............................................................................................................................................................................
Adverse events, total............................................................................................................................................................................
Serious adverse events.........................................................................................................................................................................
APPENDICES................................................................................................................................................................................................. 34
WHAT'S NEW................................................................................................................................................................................................. 37
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 37
DECLARATIONS OF INTEREST..................................................................................................................................................................... 37
SOURCES OF SUPPORT............................................................................................................................................................................... 37
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 37
INDEX TERMS............................................................................................................................................................................................... 38
Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) i

Informed decisions.

[Intervention Review]
Cell-based therapies for amyotrophic lateral sclerosis/motor neuron

disease
S Fadilah Abdul Wahid1, Zhe Kang Law2, Nor Azimah Ismail1, Nai Ming Lai3
1Cell Therapy Center, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. 2Department of Medicine, Faculty of
Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. 3School of Medicine, Taylor's University, Subang
Jaya, Malaysia
Contact address: S Fadilah Abdul Wahid, Cell Therapy Center, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Kuala
Lumpur, 56000, Malaysia. sfadilah@ppukm.ukm.edu.my.
Editorial group: Cochrane Neuromuscular Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 12, 2019.
Citation: Abdul Wahid SF, Law ZK, Ismail NA, Lai NM. Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.
Cochrane Database of Systematic Reviews 2019, Issue 12. Art. No.: CD011742. DOI: 10.1002/14651858.CD011742.pub3.
ABSTRACT
Background
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).
Objectives
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.
Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 1

Informed decisions.

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?
Background
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).

Informed decisions.

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.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. BM-MSC compared to no treatment for amyotrophic lateral sclerosis/motor neuron disease
Library
Cochrane
BM-MSC compared to no treatment for amyotrophic lateral sclerosis/motor neuron disease
Participants or population: people with probable or definite amyotrophic lateral sclerosis/motor neuron disease (treated with riluzole)
Setting: hospital
Better health.
Informed decisions.
Trusted evidence.
Intervention: BM-MSC
Comparison: no treatment
Outcomes Anticipated absolute effects* (95% CI) Relative № of Certain- Comments

effect partici- ty of
Risk with no Risk with BM-MSC (95% pants the evi-
treatment CI) (stud- dence
ies) (GRADE)
Functional impairment, assessed using a The mean The mean ALSFRS-R score — 56 ⊕⊕⊝⊝ BM-MSCs may reduce the decline
functional rating scale (change from base- ALSFRS-R score in the BM-MSC group was (1 RCT) Lowa,b in ALSFRS-R score from baseline to
line to 6 months): mean change in ALSFRS-R change in the no 3.38 points less than in 6 months.
score treatment group the no treatment group
was –6.48 points (1.22 less to 5.54 less)
Range: 48 (normal) to 0 (maximally impaired)
Follow-up: 6 months
Functional impairment, assessed using a Not measured

functional rating scale (change from base-
line to 12 months)
Muscle strength: manual muscle testing Not measured

(mean change from baseline to 12 months)
Respiratory function: change in FVC% (mean The mean change The mean change in FVC% — 56 ⊕⊕⊝⊝ BM-MSCs may have little or no ef-
change from baseline to 12 months) in FVC% in the no in the BM-MSC group was (1 RCT) Lowa,c fect on FVC% change from baseline
treatment group –0.53% more to 4 months.
Follow-up: 4 months was –10.75% (–5.37% more to 4.31%
less)
Overall survival Study population RR 1.07 64 ⊕⊕⊝⊝ BM-MSCs may have little or no
(0.94 to effect on overall survival at 6
Follow-up: 6 months 903 per 1000 966 per 1000 1.22) (1 RCT) Lowa,d months.
4

(849 to 1000)
Adverse events, total Study population RR 0.86 64 ⊕⊕⊝⊝ There may be little or no difference
Library
Cochrane
(0.62 to (1 RCT) Lowa,d in total adverse events with BM-
Follow-up: 4 months 742 per 1000 638 per 1000 1.19) MSCs compared to no treatment
(460 to 883) group.
Serious adverse events Study population RR 0.47 64 ⊕⊕⊝⊝ There may be little or no difference
(0.13 to (1 RCT) Lowa,e in serious adverse events with BM-
Follow-up: 4 months 194 per 1000 91 per 1000 1.72) MSC compared to no treatment
Better health.
Informed decisions.
Trusted evidence.
(25 to 333) group.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; BM-MSC: bone marrow mesenchymal stem cells; CI: confidence interval; FVC: forced vital ca-
pacity; RCT: randomised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
aThe study that provided data was at high risk of bias for blinding of participants and personnel, which collectively posed a serious concern for the outcomes assessed (which
require a degree of subjective judgement) and also at high risk of attrition bias.
bDowngraded one level for imprecision. The 95% CI ranged from a relative trivial change in ALSFRS to a degree of change that was considered clinically important (changes in
score of 4 or more) (Castrillo-Viguera 2010).
cDowngraded one level for imprecision. The 95% CI ranged from a substantial decrease to a substantial increase.
dDowngraded one level for imprecision. The 95% CI encompassed a moderate decrease to a moderate increase in risk.
eDowngraded one level for imprecision. The 95% CI encompassed a substantial decrease to a substantial increase in harms. Serious adverse events in the MSC group were not
considered to be treatment-related.


5

Informed decisions.

BACKGROUND was found to slow functional deterioration in some people with

ALS/MND and is approved for use in Japan, Korea and the US (Abe
Description of the condition 2014; Cruz 2018; Writing Group 2017). Many other pharmacological
agents have been tried, but without clear benefit. In addition
Motor neuron disease (MND) is a rare neurodegenerative disorder
non-pharmacological treatment, such as non-invasive ventilation,
with an annual incidence of approximately 2 per 100,000
prolongs median survival and improves quality of life in people with
population. MND affects men and women of all ages, with a peak
ALS/MND (Bourke 2006; Radunovic 2013).
incidence at 50 to 70 years of age (Logroscino 2005; Logroscino
2008). The cause of MND is unknown, but up to 10% of cases Description of the intervention
are familial (Murray 2004). The clinical features of MND are
attributable to the degeneration of neurons and corticospinal tracts Multipotential stem cells may provide an attractive therapeutic
from the primary motor cortex in the brain to the anterior horn option because of their ability to migrate into damaged neural
cells in the spinal cord and brainstem nuclei (Rabin 1999). Four tissues and promote regeneration of neurons (neurogenesis).
major categories of MND are recognised, namely amyotrophic These multipotential stem cells produce neurotrophic (growth-
lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive stimulating) factors, thus provoking the transdifferentiation of
muscular atrophy (PMA) and progressive bulbar palsy (PBP). When stem cells into neurons (Karussis 2010).
the person presents with both upper and lower motor neuron
signs, the disease is known as ALS, which is the most common Cell-based therapy can be defined as injection of cellular material
form of MND. The terms PLS and PMA are applied when the initial into a person for therapeutic purposes. Various type of cells can
presentation reflects only upper motor neuron involvement or only be used including stem cells that are used to treat degenerative
lower motor neuron involvement, respectively. PBP presents with diseases (regenerative medicine), blood cancers and bone marrow
weakness of bulbar muscles. The terminology can be confusing. In diseases (bone marrow transplantation). To date, there have been
the UK and Australia, for example, MND is both the umbrella term numerous clinical trials of the treatment of ALS/MND with cell-
for these conditions and is also used to refer to the ALS subtype. In based therapy utilising cells isolated mostly from autologous
the United States, however, ALS is the more usual umbrella term, (the person's own) bone marrow and peripheral blood, thus
but it also denotes the ALS subtype. This review uses ALS/MND. minimising the risk of rejection. The types of cells used for
implantation have been bone marrow mononuclear cells (BM-
Common clinical features of ALS/MND include wasting and MNCs; Blanquer 2012; Deda 2009; Prabhakar 2012), bone marrow-
weakness of the muscles for mastication, speech articulation and mesenchymal stem cells (BM-MSCs; Baek 2012; Blanquer 2012;
swallowing, intrinsic muscles of the hands and muscles of lower Karussis 2010; Martinez 2012; Mazzini 2003; Mazzini 2006; Mazzini
limbs. Respiratory failure due to respiratory muscle weakness is 2012), granulocyte-colony stimulating factor (G-CSF)-mobilised
a late feature, leading to death (Caroscio 1987). Rarely, ALS/MND peripheral blood mononuclear cells (M-PBMNCs; Cashman 2008;
presents with acute respiratory failure (Chen 1996). The disease is Chio 2011; Nefussy 2010), olfactory ensheathing stem cells (OESC;
virtually always fatal. Approximately half of people with ALS/MND Chen 2007; Chew 2007; Giordana 2010; Huang 2008; Piepers 2010),
die within three years from onset of symptoms, although 10% of and neural stem cells (NSCs; Feldman 2014).
people with ALS/MND live longer than 10 years (del Aguila 2003;
Turner 2003). BM-MNCs are usually separated by a density gradient method
from bone marrow aspirate obtained from the individual's hip
The exact mechanism leading to selective cell death of motor bone. Mesenchymal stem cells (MSCs) can be easily isolated from
neurons is not well understood and is likely to be multifactorial, bone marrow, placenta, muscle and fat. The cells are subsequently
involving genetic and environmental factors. Several genes have cultured for three to five weeks to provide large numbers for
been identified as the cause of familial ALS/MND, including therapeutic application. These cells can be expanded in vitro
mutations in Cu2+/Zn2+ superoxide dismutase 1 (SOD1), TAR DNA- with no risk of malignant transformation (Bernardo 2007). The
binding protein 43 (TARDBP), fused in sarcoma (FUS), c9orf72, process of obtaining M-PBMNCs involves administration of G-CSF
UBQLN2 and TANK-binding kinase 1 (TBK1) (Deng 2011; Oakes to increase the number of M-PBMNCs in the circulation, followed
2017; Renton 2014). The genetic contribution to the majority of ALS/ by their removal using a blood cell separation machine (apheresis).
MND remains unknown. The neurodegenerative process of ALS/ OESCs are extracted from human foetal olfactory bulb tissue and
MND may involve a complex interplay between genetic factors, cultured for two to three weeks. NSCs used in clinical studies are
oxidative stress, glutamatergic excitotoxicity, protein aggregation, cultured human NSCs derived from a single source human foetal
mitochondrial dysfunction, altered immune-inflammation and spinal cord tissue of approximately eight gestational weeks and
impairment of axonal transportation. The surrounding glial cells expanded serially by epigenetic means only (Feldman 2014).
have also been implicated in the pathogenesis via the release
of inflammatory mediators, impaired neuronal metabolic support Implantation of cells has been performed via several methods. The
and dysfunctional signalling pathways (Lunn 2014; Shaw 2005). All common methods include intrathecal (into the subarachnoid space
these processes eventually lead to apoptosis of motor neurons. via the spinal canal), intracortical (into the cerebral cortex) and
direct transplantation of autologous MSCs into surgically exposed
To date, there is no curative treatment for ALS/MND. Current spinal cord under general anaesthesia. Studies have shown that
treatment approaches focus on relieving symptoms to improve the direct transplantation of autologous cells into the spinal cord is
quality of life of those affected. Riluzole, an antiglutamate agent, is well tolerated and feasible in people with ALS/MND (Feldman 2014;
the most commonly used pharmacological treatment for ALS/MND. Mazzini 2012).
It has a small beneficial effect on bulbar function, limb function
and survival, but no effect on muscle strength (Bensimon 1994; Several clinical trials have provided important insights into the
Goodall 2006; Miller 2012). In addition, edavarone (an antioxidant) safety and feasibility of stem cell mobilisation and transplantation

Informed decisions.

in people with ALS/MND. Previous reviews supported the use of the therapeutic application of stem cells for this devastating
cell-based therapy as a means of delaying the disease course in incurable disease. Early clinical trials have suggested that stem
ALS/MND, mainly based on preclinical animal models (Goutman cells could have the potential to replace and repair damaged
2015; Thonhoff 2009). Single-arm and small clinical trials observed motor neurons in people with ALS/MND (Martinez 2012; Mazzini
no clinical benefits. Limited data from non-RCTs involving a 2003; Mazzini 2015). Moreover, the procedures of expansion and
small number of people with ALS/MND and a short-term follow- transplantation of these cells into people with ALS/MND are
up period suggested that cell-based therapy slowed the rate of well tolerated and feasible. However, most of the clinical trials
disease progression (Lunn 2014). Uncertainties remain, however, involved small numbers of participants, which can produce false-
regarding its ability to achieve functional improvement and its positive results, or overestimate the magnitude of an association;
long-term safety profile; in particular, whether this mode of therapy consequently, the results have been inconsistent. Additionally,
is associated with acceleration of disease progression (Lunn 2014). small trials may fail to detect rare adverse events. Combining
available data in a systematic review may increase the likelihood
How the intervention might work of detecting a true effect of the intervention, thus allowing
meaningful conclusions to be drawn. It is also important to
There are two possible mechanisms by which stem cell therapy
know whether cells derived from different sources have different
may help in the treatment of ALS/MND. First, by using progenitor
impacts on clinical outcomes among people with ALS/MND.
cells that have been generated ex vivo to regenerate dying neuronal
For example, stem cells obtained from different sources may
cells. Experimental observations showed that transplanted stem
possess different biological properties (plasticity, self-renewal,
cells and mononuclear cells have the capacity to stimulate the
differentiation, homing, migration and secretion of trophic factors)
regenerative processes of motor neurons (Mazzini 2003). In animal
and different immunological properties (modulating immune
models of ALS/MND, stem cell transplantation can significantly
response). These differences may be attributed to the inherent
slow the progression of the disease and prolong survival (Mazzini
biological properties of the stem cells or changes that occur during
2003). Increasing numbers of preclinical studies have shown that
enrichment and processing. Moreover, questions regarding the
transplanted stem cells are capable of migrating to regions of
optimal treatment approaches, including the cell dose, phenotype,
experimentally induced nerve injury, where they are able to
preparation and delivery system, remain to be answered (Abdul
proliferate and differentiate into neurons and glial cells (Jiang 2002;
2018).
Liu 2000; McDonald 1999; Terada 2002; Woodbury 2000). The types
of stem cell that have been tested in preclinical models include BM- This systematic review set out to determine the efficacy, feasibility
MSCs, MSCs, cord blood stem cells, embryonic stem cells, neural and safety of cell-based therapy in people with ALS/MND. The
stem and progenitor cells, human glial restricted progenitors, and findings of this review may facilitate design of the optimal cell-
induced pluripotent stem cells (IPCs). based therapy programme for people with ALS/MND as well as
identify critical areas for improvement and recommendations for
Second, stem cells promote the survival of existing neurons. MSCs
future clinical trials. The review was first published in 2015 when
are very attractive candidates for cell therapy in ALS/MND because
the first clinical trials of cell-based therapies were still in progress
of their great plasticity (Chen 2008), and immunomodulatory
(Abdul-Wahid 2016). We updated it in 2019 to incorporate evidence
properties (Mazzini 2012). MSCs can induce a neuroprotective
now available from randomised controlled studies.
microenvironment via anti-inflammatory and immunosuppressive
effects on astrocytes and microglial cells (Uccelli 2008). MSCs
OBJECTIVES
release soluble molecules such as cytokines and chemokines, and
express immune-relevant receptors such as chemokine receptors To assess the effects of cell-based therapy in people with ALS/MND
and cell adhesion molecules that ameliorate inflammation and compared with a placebo or no treatment.
stimulate the survival of neuronal cells (Uccelli 2008). Preclinical
data have shown that MSCs are capable of transdifferentiation into METHODS
neurons and glial cells both in vitro and in vivo (Black 2001; Kim
2002; Sanchez-Ramos 2000). In addition, NSCs have the ability to Criteria for considering studies for this review
generate immunomodulatory cells, growth-factor-releasing cells
and functional support cells to modify motor neuron survival and Types of studies
activity (Gowing 2011). We included randomised controlled trials (RCTs), quasi-RCTs
and cluster RCTs. Quasi-random methods of assignment to
Most studies on the pathogenesis of ALS/MND thus far have been interventions are systematic methods that are not truly random,
in animals. There are many limitations when extrapolating the such as allocation using alternation, date of birth, day of visit or
findings observed in animal models into humans. First, there medical record number.
are interspecies differences in neuronal physiology and specific
gene-splicing patterns (Hardingham 2010). Second, there is an Types of participants
overemphasis on models based on rat SOD1, when most cases of
human sporadic ALS/MND may not have a SOD1 defect. In this We included people of any age with a diagnosis of definite or
respect, stem cells could be used to model disease, allowing us to probable ALS/MND according to accepted criteria, such as the
further explore the pathophysiological process of ALS/MND. revised El Escorial World Federation of Neurology criteria (Brooks
2000).
Why it is important to do this review
Types of interventions
The lack of effective pharmacological treatment for ALS/MND
Mononuclear cells or stem cells compared with a placebo or no
and compelling preclinical data have provided a rationale for
additional treatment. We would have permitted the use of co-
Informed decisions.

interventions including standard treatment such as riluzole and We applied no language restrictions. We included studies reported
symptomatic treatment, provided that they were administered to as full-text publications as well as those published as abstracts and
each group equally. proceedings.
Types of outcome measures We also conducted a search of the following trials registries
US National Institutes of Health Clinical Trials Registry
Primary outcomes
(www.clinicaltrials.gov), and the World Health Organization
1. Functional impairment, assessed using a functional International Clinical Trials Registry Platform (ICTRP; apps.who.int/
rating scale (change from baseline to six months): trialsearch/) to identify other ongoing and unpublished studies.
change in functional rating scale, such as the Amyotrophic
Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) For the first version of the review (Abdul-Wahid 2016), we searched
(Cedarbaum 1999) at 6 or 12 months. the National Institute for Health Research Database of Abstracts
and Reviews of Effects (DARE) and Health Technology Assessments
A change in ALSFRS-R score of 4 or higher is considered clinically (HTA) database to identify reviews and assessments for inclusion
important (Castrillo-Viguera 2010). in the 'Discussion' section. We searched National Health Service
Economic Evaluation Database (NHS EED) for any available cost
Secondary outcomes information for the 'Discussion' section. We did not search these
1. Functional impairment, assessed using a functional rating databases for this update as they are no longer included in the
scale (change from baseline to 12 months): change in Cochrane Library.
functional rating scale, such as the ALSFRS-R (Cedarbaum 1999).
Searching other resources
2. Muscle strength: change in manual muscle testing of the upper
and lower limbs (Medical Research Council (MRC) grade) at 6 and We searched for additional references in reference lists of
12 months. all primary studies and review articles. We contacted the
authors of RCTs and other experts in the field to obtain any
3. Respiratory function: change in upright forced vital capacity
additional published or unpublished studies. We searched relevant
(FVC) at 6 and 12 months.
manufacturers' websites for trial information to identify further
4. Nerve conduction: change in compound muscle action relevant studies. In addition, we handsearched journals for
potential (CMAP), neurophysiological index (NI), combined relevant articles: Cytotherapy (January 1999 to June 2018), Cell
motor index (CMI), motor unit number estimation (MUNE) and Transplantation (Issue 1, 2001 to Issue 6, 2018), Cell Stem Cell (Issue
motor unit number index (MUNIX) at 6 and 12 months (Escorcio- 1, 2007 to Issue 6, 2018) and Stem Cells (Issue 1, 1993 to Issue 6,
Bezerra 2016; Gawel 2016; Stein 2016). 2018).
5. Mood state and quality of life: change in mood state and
quality of life using the Profile of Mood State (POMS) and Data collection and analysis
quality of life scale questionnaires (such as ALS Assessment
Questionnaires, ALSAQ-40 or ALSQ5, Short-Form 36 (SF-36) Selection of studies
Health Survey and EQ-5D) at 6 and 12 months (Jenkinson 2000; Two review authors (SFAW and ZKL) independently screened
Jenkinson 2007; Rabin 2001; Ware 1992). titles and abstracts of all studies identified from the first round
6. Structural changes in serial magnetic resonance imaging of searching. We coded potentially relevant studies or studies
(MRI): such as T2-weighted and Fluid-Attenuated Inversion that required further assessments as 'retrieve' based on the
Recovery (FLAIR) hyperintense signals in corticospinal tracts, relevance of the population, intervention and outcomes to our
precentral and frontal cortex at 6 and 12 months. review question. We coded studies clearly not relevant as 'do not
7. Overall survival: at 6 and 12 months. retrieve'. Two review authors (SFAW and ZKL) inspected the full-
8. Adverse events: including an inflammatory reaction at text versions of the studies coded 'retrieve' to further identify
the cell injection site, cardiovascular and thromboembolic trials to be included in our meta-analysis, based on the relevance
complications, adverse events, serious adverse events and the of the population, intervention, comparison and study design.
rate of withdrawal from the study. Among studies retrieved but excluded, we recorded reasons for
exclusion. We resolved any disagreement through discussion and
Search methods for identification of studies did not require consultation with a third person. We identified
and excluded duplicates, and collated multiple reports of the
Electronic searches same study, making each study the unit of interest in the review
We searched the following databases: rather than each report. We recorded the selection process in
sufficient detail to complete a PRISMA flow diagram (Moher 2009)
1. the Cochrane Neuromuscular Specialised Register via the and Characteristics of excluded studies table.
Cochrane Register of Studies (CRS-Web; 31 July 2019; Appendix
1); We did not identify any included studies for quantitative analysis.
We provide a qualitative narration of the excluded studies in the
2. the Cochrane Central Register of Controlled Trials (CENTRAL) via
Discussion.
the CRS-Web (31 July 2019; Appendix 2);
3. MEDLINE (1946 to 30 July 2019; Appendix 3); Data extraction and management
4. Embase (1974 to 29 July 2019; Appendix 4). Two review authors (SFAW and ZKL) independently extracted the
following study characteristics from included studies according to
the methods described in our protocol (Abdul Wahid 2015).
Informed decisions.

1. Methods: study design, date and duration, details of any 'run-in' similar outcomes measured on different scales. In this case, we
period (time in a study before participants receive treatment), would have adjusted all the scales to achieve a consistent direction
number of study centres and location, setting, withdrawals. of effect.
2. Participants: number, age (mean or median age, range), gender,
disease severity, diagnostic criteria, inclusion and exclusion We planned to undertake meta-analyses only where the
criteria. participants, intervention, comparison and outcomes were similar
enough for pooling to be meaningful, and to only narratively
3. Interventions: intervention and co-intervention and
describe skewed data reported as medians and interquartile
comparison.
ranges.
4. Outcomes: primary and secondary outcomes specified and
collected, and time points reported. Unit of analysis issues
5. Notes: date trial conducted, funding for trial, notable conflicts of For cluster RCTs (in other words, trials in which the assignment to
interest of trial authors. intervention or control group was made at the level of the unit/ward
rather than the individual participant), we would have assessed
Two review authors (SFAW and ZKL) independently extracted the
whether the study authors had made appropriate adjustments for
outcome data and noted in the Characteristics of included studies
the effects of clustering, using appropriate analysis models such
table if outcome data were not reported in a usable way, with
as the Generalized Estimating Equation model. We would have
disagreements resolved by consensus or by involving another
inspected the width of the standard error (SE) or 95% CI of the
review author (NAI). One review author (NAI) transferred data into
estimated treatment effects to double-check the possible unit of
Review Manager 5 (RevMan 5) software (Review Manager 2014),
analysis in the study. If we found an inappropriately small SE or a
one review author (SFAW) checked the outcome data entries, and
narrow 95% CI, we would have asked the authors of the study to
another review author (NML) spot-checked study characteristics for
confirm the unit of analysis.
accuracy against the trial report.
If no adjustment had been made for the effects of clustering,
If reports had required translation, the authors would have
we would have performed adjustments by multiplying the SEs
extracted data from the translation provided, with data cross-
of the final effect estimates by the square root of the 'design
checked against the original report if possible.
effect', represented by the formula, 1 + (M – 1) × ICC, where M
Assessment of risk of bias in included studies is the mean cluster size (number of participants per cluster) and
ICC is the intracluster correlation. The mean cluster size (M) from
Two review authors (NML and SFAW) independently assessed each trial would be determined by dividing the total number of
the risk of bias for each study according to the domains listed participants by the total number of clusters. We planned to use an
below, as outlined in the Chapter 8 of the Cochrane Handbook for assumed ICC of 0.10, as we consider this to be a realistic general
Systematic Reviews of Interventions (Higgins 2011a), with resolution estimate that is derived from previous studies on implementation
of disagreement by discussion or by involving another author (NAI). research (Campbell 2001). We would have combined the adjusted
final effect estimates from each trial with their SEs in meta-analyses
1. Random sequence generation.
using generic inverse variance methods, as stated in the Cochrane
2. Allocation concealment. Handbook for Systematic Reviews of Interventions (Higgins 2011a).
3. Blinding of participants and personnel.
4. Blinding of outcome assessment. If the determination of the unit of analysis was not possible, we
planned to include the studies concerned in a meta-analysis using
5. Incomplete outcome data.
the effect estimates reported by the authors. We would also have
6. Selective outcome reporting. performed sensitivity analyses to assess how the overall results
7. Other bias, such as premature termination and extreme baseline were affected by the removal of the studies in which adjustment of
imbalance. unit of analysis was appropriate but not possible and the unit of
analysis was unknown.
We made a judgement on each of the criteria above as to whether
the study was at high, low or unclear risk of bias. We assessed Dealing with missing data
blinding for each category of outcomes (objective and subjective)
separately when possible. We completed a 'Risk of bias' table If key information were missing, such as study characteristics,
for each eligible study and resolved disagreement among review methods or outcome data, we planned to contact investigators
authors through discussion leading to consensus. We presented an to obtain the relevant information. Where this was not possible,
overall assessment of the risk of bias using the 'Risk of bias' graph we would have conducted a deterministic sensitivity analysis at
and the 'Risk of bias' summary. the study level by adopting an approach as recommended in
chapter 16.2.3 of the Cochrane Handbook for Systematic Reviews
Measures of treatment effect of Interventions (Higgins 2011a) for handling sensitivity analysis
for continuous outcomes, for instance, our primary outcome of
For dichotomous data (adverse event, serious adverse event and change in functional rating scales, such as the ALSFRS or Expanded
overall survival), we used risk ratio (RR) with 95% confidence Disability Status Scale (EDSS) measured at six months. In this
intervals (CI) to measure outcome estimates on the same scale. approach, we would have assumed a fixed difference of 10%
For continuous data (ALSFRS-R score change, FVC % change, between the mean of the missing data and the observed mean of
SF-36 change), we used mean differences (MD) with 95% CIs for the available data in the intervention arm as well as the control arm,
conceptually similar outcomes measured on the same scale, or with the direction of the difference in opposition to the observed
standardised mean differences (SMD) with 95% CIs for conceptually direction of the effect size in the analysis. Following is a possible
Informed decisions.

scenario: in our analysis of the available data, the intervention Our judgement on the overall certainty of the body of evidence
arm has a higher mean, indicating that the effect favours the was guided by the five GRADE considerations, namely limitations
intervention arm (higher value in the scale indicating a better in study design, consistency of effect, imprecision, indirectness
outcome). In this instance, we would have performed the sensitivity and publication bias. We used methods and recommendations
analysis by assuming that the mean of the missing data in the described in Chapter 12 of the Cochrane Handbook for Systematic
intervention arm was 10% lower than the mean of the available Reviews of Interventions (Higgins 2011b) using the GRADE profiler
data in the intervention arm, and accordingly, the mean of the (GRADEpro) software (GRADEpro 2018). We downgraded the
missing data in the control arm was 10% higher than the mean certainty of evidence once if a GRADE consideration was present to
of the available data in the control arm. We would then have a serious degree and twice if very serious. We justified decisions to
pooled the imputed data with the observed data for each arm downgrade or upgrade the certainty of evidence using footnotes in
and re-assessed the imputed effect estimate having compared the the 'Summary of findings' table.
imputed pooled estimate of the two arms. If the effect estimate of
the study changed substantially following our sensitivity analysis Subgroup analysis and investigation of heterogeneity
using this approach, we would have considered the study at high We planned to carry out a subgroup analysis based on the type of
risk of attrition bias. At the review level, we would have conducted a cell-based therapy received (i.e. BM-MNCs, BM-MSCs, M-PBMNCs,
sensitivity analysis to explore the impact of including such studies OESCs or NSCs). We would also have conducted a subgroup
with high risk of attrition bias in the overall pooled estimates of the analysis based on delivery method (i.e. intrathecal, intracranial,
major outcomes. intraspinal and intravenous) and for the primary endpoint that
was measured at two separate time points. We would have used
Assessment of heterogeneity
functional scales, such as the EDSS and ALSFRS, FVC, quality of life
We would have used the I2 statistic to measure heterogeneity scores, MRI changes, survival rate, neurophysiological index and
among the trials in each analysis. If we had identified substantial adverse events as outcome measures.
unexplained heterogeneity (as shown by an I2 statistic greater than
50%), we would have explored possible causes by prespecified We planned to use the formal test for subgroup interactions in
subgroup analyses (see Subgroup analysis and investigation of Review Manager 5 (Deeks 2011).
heterogeneity).
Sensitivity analysis
Assessment of reporting biases We planned to carry out the following sensitivity analyses if the
If we had been able to pool more than 10 trials, we would have review included sufficient studies.
created a funnel plot to explore possible publication biases. If we
1. Repeat the analysis excluding studies at high risk of selection
had found significant asymmetry in the funnel plot, which might
and attrition biases.
indicate possible publication bias, we would have reported this
with a note of caution in the discussion, taking into account the area 2. Repeat the analysis with a random-effects model.
of the void in the funnel plot. We did not plan to further explore 3. Repeat the analysis excluding unpublished studies.
publication bias using statistical methods in view of the limitations
of these methods in the presence of the relatively small number of If the overall results were affected substantially by the sensitivity
studies in a typical systematic review (Higgins 2011a). analysis, we would have placed a note of caution in our discussion
and conclusions regarding the certainty of our estimates, and
Data synthesis proposed a need for further research where appropriate to explore
the possible sources of variation in the outcome estimates.
We would have performed meta-analyses in Review Manager 5
using a fixed-effect model (Review Manager 2014). If suitable data RESULTS
had been available, we planned to perform a sensitivity analysis
to assess the change in the overall results with a random-effects Description of studies
model.
Results of the search
'Summary of findings' table
The previous version of this review identified no studies for
We created a 'Summary of findings' table comparing cell-based inclusion. In 2019, we identified 151 new papers from database
therapy versus placebo or no additional treatment using the searches as potentially relevant and after we reviewed these, two
following outcomes. RCTs (112 participants) met the inclusion criteria for the review.
Of the two studies eligible for inclusion, one study contributed
1. Functional impairment, assessed using a functional rating outcome data (Oh 2018), as the outcome data of the other study
scale (change from baseline to six months): ALSFRS. were not presented in an extractable form for meta-analysis
2. Functional impairment, assessed using a functional rating (Gothelf 2017). The results of Gothelf 2017 were published as an
scale (change from baseline to 12 months): ALSFRS. abstract only and conclusions were stated without any numbers
3. Muscle strength: manual muscle testing (at six months). being given. We also identified four ongoing trials (NCT01254539;
4. Respiratory function: change in upright FVC (at six months). NCT02286011; NCT02290886; NCT03280056). Figure 1 shows a
summary of the results of the search.
5. Overall survival (at six and 12 months).
6. Adverse events (at any given time point).


Informed decisions.

Figure 1. Study flow diagram.

Included studies Methods
See Characteristics of included studies table for full details of the Both studies were phase 2, parallel-group RCTs.
included studies. The following are major characteristics of the
included studies. Population
Both studies enrolled adults (aged 18 to 75 years) with probable
Country
or definite diagnosis of ALS/MND, following the revised El Escorial
One study was conducted in the US (Gothelf 2017), the other in the World Federation of Neurology criteria (Brooks 2000).
Republic of Korea (Oh 2018).

Informed decisions.

Interventions and comparators participants (Mazzini 2015), MSC-NTF in 38 participants (Karussis

2013; Petrou 2015), and BM-MSC in 15 participants (Gabr 2017).
The two included studies made two different comparisons. Gothelf
2017 compared autologous mesenchymal stem cells secreting 2. One study assessed the safety and feasibility of intravenous
neurotrophic factors (MSC-NTF) cells by combined intramuscular and intrathecal injections of BM-MSCs in people with ALS/MND
and intrathecal administration (dosage not stated) with placebo (Nabavi 2019).
(follow-up period: 24 weeks). Oh 2018 compared BM-MSCs (two
See Characteristics of excluded studies table.
intrathecal injection with 1 × 106 cells per kilogram bodyweight at
an interval of 26 days) with riluzole treatment with riluzole alone Ongoing studies
(follow-up period: 6 months).
Four trials are ongoing (NCT01254539; NCT02286011;
Outcomes NCT02290886; NCT03280056). NCT01254539 is a randomised,
double-blind trial to assess the feasibility and safety of intraspinal
As both studies were phase 2 trials, safety outcomes were the
and intrathecal infusion of autologous bone marrow stem cells.
primary outcomes of interest, and these included the assessment
NCT02286011 is a phase 1 randomised, double-blind, controlled
of overall adverse effects (Gothelf 2017; Oh 2018), and serious
clinical trial on intramuscular infusion of autologous BM-MNC.
adverse effects (Oh 2018). Additionally, Gothelf 2017 evaluated
NCT02290886 is a phase 1/2 randomised, placebo-controlled,
changes in function as measured by ALSFRS and changes in vital
triple-blind trial to evaluate the safety and efficacy of intravenous
capacity, both measured at 24 weeks as secondary outcomes. Oh
autologous adipose tissue-derived MSCs at three different doses
2018 evaluated changes in the degree of disability as measured by
(one million, two million, and four million autologous MSCs).
the ALSFRS-R as the primary outcome, with changes in Appel scale,
Finally, NCT03280056 is a phase 3, randomised, double-blind,
FVC, and change in health-related quality of life as measured by the
multicentre trial to evaluate the safety and efficacy of three
change in SF-36, as secondary outcomes.
intrathecal administrations of MSC-NTF cells at a bi-monthly
Excluded studies intervals, compared to placebo. See Characteristics of ongoing
studies table.
We assessed and excluded five studies, reported in 12 full-text
articles, as follows. Risk of bias in included studies
1. Four non-randomised trials (11 records). These trials Both included studies were parallel-group, randomised controlled,
investigated the safety and efficacy of foetal human NSCs in six phase 2 trials, with one labelled as "double-blind" (Gothelf 2017),
and another open-label and assessor blinded (Oh 2018). For a
summary of 'Risk of bias' assessments, see Figure 2.


Informed decisions.

Figure 2. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation (selection bias) Incomplete outcome data (attrition bias)
We judged one study at low risk of selection bias, as the participants We judged one study to have high risk of attrition bias (Oh 2018).
were randomised using an interactive web response system (Oh The overall dropout rate was high and the number of dropouts was
2018). Authors of the other study did not mention the methods unequal between the two groups. Four participants in the control
of sequence generation and allocation, hence we accorded it an group (withdrawal: 2; death: 1; serious adverse event: 1) and one
unclear risk of selection bias (Gothelf 2017). participant in the MSC group (withdrawal: 1) were excluded from
full analysis because these events occurred before the baseline
Blinding (performance bias and detection bias) visit. The number of participants analysed was not stated in the
We judged one study to have a high risk of performance bias, as records obtained for the other included study (Gothelf 2017), hence
it was stated to be open label, but at low risk of detection bias, we judged the risk of bias to be unclear.
as neurologists and evaluators who were blinded to treatment
Selective reporting (reporting bias)
assignments performed the outcome assessment (Oh 2018).
Another study was labelled "double-blind" (Gothelf 2017); however, We judged Oh 2018 to have low risk of reporting bias, as the
there was no detailed description of the blinding mechanism and published article published all the endpoints and outcomes
so we accorded it an unclear risk of performance bias. The risk of specified in the protocol, such as ALSFRS-R score change, FVC%
detection bias was unclear, as the authors did not clearly mention change, and SF-36 change; the trial authors also reported adverse
the blinding status of the outcome assessors. events, serious adverse events, and overall survival (the last as a
post hoc analysis). We judged Gothelf 2017 to have a high risk of
bias for selective reporting, because the outcome data were not
presented in an extractable form for meta-analysis and attempts to
contact study authors were unsuccessful.
Informed decisions.

Other potential sources of bias Mood state and quality of life
We screened for other potential sources of biases including extreme The study did not measure mood and did not report quality of life
baseline imbalance and unit of analysis issues. One included study at six or 12 months.
was at low risk of other potential sources of bias (Oh 2018), while the
information for another study, presented in abstract form as well as The study reported mean changes in SF-36 scores at four months.
trial registry, were insufficient for an assessment of other potential There was no clear difference in the changes in SF-36 between the
biases (Gothelf 2017). two groups (MD 2.77, 95% CI –3.50 to 9.04; 57 participants; Analysis
1.3).
Effects of interventions
Structural changes in serial magnetic resonance imaging
See: Summary of findings for the main comparison BM-MSC
The study did not measure structural changes in serial MRI.
compared to no treatment for amyotrophic lateral sclerosis/motor
neuron disease Overall survival
Autologous bone marrow-mesenchymal stem cells versus no In the BM-MSC group, 32/33 participants were alive at six months,
treatment compared to 28/31 participants in the control group. One death
in the BM-MSC group and two deaths in the control group were
One study, which had 64 participants, compared BM-MSC injection caused by respiratory failure as a result of disease progression.
to no treatment (Oh 2018). Participants in both groups received One control group participant died from a sudden cardiac arrest
riluzole. This study did not report clinical outcomes at 12 months before the treatment phase of the study. BM-MSC had little or no
after cell injection and structural outcomes measured by MRI, which effect on overall survival at six months (RR 1.07, 95% CI 0.94 to 1.22;
we had proposed in our protocol (Abdul Wahid 2015). Outcomes 64 participants; low-certainty evidence; Analysis 1.4; Summary of
were measured at four months, other than the ALSFRS-R score, findings for the main comparison). The study did not report overall
which was measured at four and six months. See Summary of survival at 12 months.
findings for the main comparison.
Adverse events
Primary outcomes
Total adverse events
Functional impairment, assessed using a functional rating scale
(change from baseline to six months) The common adverse events in the MSC group at six months
were influenza-like illness (seven participants), back pain (five
ALSFRS-R
participants) and musculoskeletal pain (five participants). The
The mean decline in ALSFRS-R score (range: 48 (normal) to proportion of participants with any adverse event was 9% (3/33,
0 (maximally impaired) from baseline to six months after cell four events) in the BM-MSC group, and included headache (two
injection was slightly less in the BM-MSC group than in the control events), pyrexia (one event), and pain at administration site (one
group (MD 3.38, 95% CI 1.22 to 5.54; 56 participants; low-certainty event); these adverse drug reactions were mild and transient,
evidence; Analysis 1.1). We downgraded the certainty of evidence occurred within 48 hours postinjection, and were self-limited or
one level each for risk of bias and imprecision. A change in ALSFRS- subsided with simple analgesics within 48 hours of treatment.
R score of 4 or more points is considered clinically important There was no clear difference in the proportion of participants with
(Castrillo-Viguera 2010). any adverse event between the two groups (RR 0.86, 95% CI 0.62
to 1.19; 64 participants; low-certainty evidence, downgraded one
Secondary outcomes level each for risk of bias and imprecision; Analysis 1.5; Summary of
Functional impairment, assessed using a functional rating scale findings for the main comparison).
(change from baseline to 12 months)
Serious adverse events
The included study did not measure outcomes beyond six months.
The incidence of serious adverse events during the entire follow-
Muscle strength up period was 9% (3/33, three events) in the MSC group versus
19% (6/31, six events) in the control group; serious adverse events
The study did not report data for muscle strength. in the MSC group were not considered to be treatment-related.
Respiratory function
There was no clear difference in serious adverse events between
the two groups (RR 0.47, 95% CI 0.13 to 1.72; 64 participants; low-
The study did not measure respiratory function at six or 12 months. certainty evidence, downgraded one level each for risk of bias and
imprecision; Analysis 1.6).
There was no clear difference between the two groups in the
changes in FVC% from baseline to four months (MD –0.53, 95% CI – Four deaths occurred during the six-month follow-up period: 1/33
5.37 to 4.31; 56 participants; low-certainty evidence; Analysis 1.2). participants in the MSC group (respiratory failure at five months
We downgraded the certainty of the evidence one level each for risk postinjection, related to disease progression) and 3/31 participants
of bias and imprecision. in the control group (two of respiratory failure and one of sudden
cardiac arrest before visit 3).
Nerve conduction
The study did not measure nerve conduction.

Informed decisions.

Autologous mesenchymal stem cells secreting neurotrophic implantation, which will be critical in designing optimal cell-based
factors versus placebo therapy for people with ALS/MND, remain unclear.
Gothelf 2017 investigated the effects of MSC-NTF versus placebo Certainty of the evidence
in 48 participants. The trial reported an improvement in ALSFRS-
R slope of decline in the treatment group with no improvement The certainty of evidence was low for all major outcomes, with risk
in the placebo group, but provided no numerical data. Gothelf of bias and imprecision as the main downgrading factors, due to
2017 also reported that there were no deaths or treatment-related high risk of bias in blinding of participants and personnel as well as
serious adverse events. Treatment-related adverse events were incomplete outcome data, and also because the range of plausible
mostly expected and transient, but the report did not elaborate estimates, as shown by the 95% CIs, encompassed a range that
further. We emailed the contact author twice in 2018 for additional would likely result in different clinical judgements and decisions.
information, but did not obtain a response. This, in turn, reflected the fact that there was only a single included
study of limited sample size with some risk of bias concerns.
DISCUSSION
Potential biases in the review process
Summary of main results We performed comprehensive searches in the Cochrane
We identified two RCTs of cell-based therapy in ALS/MND. The total Neuromuscular Specialised Register, CENTRAL, MEDLINE and
number of participants was 112; however, one trial was published Embase. Research conducted to answer the review question is
as an abstract which did not provide numerical outcome data. Our still in its early stages, with several phase 1 and phase 2 studies
findings are from one trial of intrathecal BM-MSCs (Oh 2018), which identified, although only two phase 2 RCTs were published to-date,
involved 64 participants and reported outcomes after four or six with four ongoing studies. Despite our comprehensive searches, it
months. is possible that we missed some relevant articles and conference
presentations not listed in the databases above or not captured in
People with ALS/MND who received intrathecal BM-MSCs appeared the handsearching process.
to have a small but statistically significant reduction in functional
impairment as measured by changes in ALSFRS-R scores over four Agreements and disagreements with other studies or
or six months, with no clear differences compared to the control reviews
group in change in per cent predicted FVC, change in quality of life
measured by the SF-36, survival at six months, or total and serious As most human studies to date focus on the safety of various
adverse events (Summary of findings for the main comparison). types of cell-based products and the feasibility of the surgical
The study did not measure muscle strength. It is uncertain if the implantation technique; these issues have been the focus of
difference in ALSFRS-R is clinically meaningful, since the MD was previous reviews. Despite the lack of reports of harms of cell-based
3.38 (95% CI 1.22 to 5.54) at six months, which was less than the therapy, data on efficacy in humans are still very limited. Preclinical
4-point change previously considered by people with ALS/MND to animal studies of stem cell therapy show promising efficacy of stem
be the minimal clinically important change (Castrillo-Viguera 2010). cell in ALS/MND but, in contrast, there is a lack of high-certainty
Furthermore, there is imprecision in the effect size estimates as the evidence on the efficacy of stem cell therapy for people with ALS/
95% CI ranges from a relative trivial change in ALSFRS to a degree MND, due to the paucity of high-quality RCTs.
of change that is considered clinically important.
One meta-analysis of nine preclinical in vivo studies and 12
A second RCT with 48 participants reported that combined retrospective descriptive clinical studies that were published
intrathecal and intramuscular autologous MSC-NTF led to an between March 2009 and March 2015 confirmed the efficacy of stem
improvement in the ALSFRS-R slope of decline in the treatment cell therapy in improving survival in animal models (transgenic
group, with no improvement in the placebo group (Gothelf 2017). mice expressing human mutated superoxide dismutase 1), where
There were no deaths, treatment-related serious adverse events an MD of 9.79 days (95% CI 4.45 to 15.14) in lifespan favoured stem
or transient treatment-related adverse events. However, the result cell therapy (Moura 2016). In contrast, the data in the Moura 2016
was only published as an abstract at the time of this review and we review from clinical studies were insufficient to assess effectiveness
were thus not able to include this study in the quantitative analysis. of stem cell therapy, and could only demonstrate itsfeasibility
and "the absence of serious adverse events". However, even this
Overall completeness and applicability of evidence conclusion should be interpreted with caution because all clinical
studies were heterogeneous and of an unsatisfactory quality.
This systematic review showed that there is a lack of high-
certainty evidence to support the use of cell-based therapy for Jeong 2015 performed a meta-analysis of 11 single-arm studies of
people with ALS/MND. Uncertainties remain as to whether this stem cell-based therapy in people with ALS/MND. This single-arm
mode of therapy is capable of restoring muscle function, slowing meta-analysis showed that the pooled MD in ALSFRS from baseline
disease progression and improving survival in people with ALS/ was decreased by 3.3 points (95% CI –5.38 to –1.22) in which
MND. Although low-certainty evidence from one RCT showed that ALSFRS declined 0.4 points per month, while pooled MD in FVC
intrathecal BM-MSC probably improves disability in people with from baseline was decreased by 14% (95% CI –19% to –6%), mean
ALS/MND compared to a control group, this was a small phase 2 decline in FVC was 1.2% per month. According to natural history
trial, which cannot be used to establish efficacy. data, the ALSFRS score declines 1.01 points and FVC declines by
2.7% per month in people with ALS/MND. The authors of Jeong
Currently, the data regarding the neuroprotective properties of 2015 concluded that stem cell therapy in people with ALS/MND can
different cell-based products are limited. Furthermore, the key slow disease progression compared to natural history, based on
elements, including cell source, phenotype, dose and method of single-arm clinical studies.

Informed decisions.

Taken together, based on evidence from non-RCTs, the previous = 0.0111, 10 participants; 87.76 (standard deviation (SD) 10.45)
systematic reviews concluded that the effectiveness of stem cell months in the BM-MNC group versus 57.38 (SD 5.31) months in the
therapy for people with ALS/MND has not been established and control group) (Martinez 2009; Sharma 2015). A subgroup analysis
needs re-evaluation. of the intervention arm revealed that younger age at disease onset
(less than 50 years), limb onset (compared to bulbar onset), and
The findings of the present systematic review appear in line with concurrent lithium therapy were associated with longer survival.
two preliminary studies that evaluated safety and feasibility of The impact of cell-based therapy on survival of people with ALS/
cell transplantation procedures into the brain, spinal cord and MND, in particular the effect of the different types of cell-based
thecal sac of people with ALS/MND (Goutman 2015; Lunn 2014). products and transplantation regimens needs to be examined in
These single-arm, small clinical phase 1/2 trials showed that, in future RCTs.
general, direct cell implantation into the cerebral cortex, spinal
cord and thecal sac of people with ALS/MND appeared feasible and Four ongoing RCTs are addressing some of these key issues related
was not associated with an acceleration in disease progression, to cell treatment protocols in people with ALS/MND. These trials are
although there are great uncertainties in the findings, due to the expected to be completed between 2019 and 2021. NCT01254539
non-randomised and preliminary nature of the trials. is a randomised, double-blind trial to assess the feasibility and the
security of the intraspinal and intrathecal infusion of autologous
Studies have evaluated a variety of cell-based products designed bone marrow stem cells. NCT02286011 is a phase 1 randomised,
to either replace the lost motor neurons or improve the metabolic double-blind, controlled clinical trial on intramuscular infusion of
supply of the affected neurons, thus delaying neuronal death. autologous BM-MNC. NCT02290886 is a phase 1/2 randomised,
MSCs, obtained mainly from autologous bone marrow, are the most placebo-controlled, triple-blind trial to evaluate the safety and
frequently used cell type in clinical trials because they are readily efficacy of intravenous autologous adipose tissue-derived MSCs in
available in large numbers, release growth factors and are non- three different doses (one million, two million, and four million
immunogenic. In people with ALS/MND, no serious adverse effects autologous MSCs). Finally, NCT03280056 is a phase 3, randomized,
and no detrimental effects on neurological function occurred double-blind, multicentre trial to evaluate the safety and efficacy
following intraspinal transplantation of variable doses of MSCs (7 × of three intrathecal administrations of NurOwn (MSC-NTF cells) at
106 to 152 × 106 cells). Some trials reported improvement in motor a bi-monthly interval, compared to placebo.
function in people with ALS/MND (Karussis 2010; Oh 2015; Petrou
2015). AUTHORS' CONCLUSIONS
Conflicting findings exist regarding the effect of OESC Implications for practice
transplantation in people with ALS/MND. Two non-randomised
clinical studies reported favourable outcomes: Huang 2008 Limited evidence of very low-to-low certainty from a single
reported a significantly greater reduction in functional randomised controlled trial shows that autologous bone marrow-
deterioration three to four months post OESC transplantation (15 mesenchymal stem cells treatment may reduce the decline in
participants) than in an untreated control group (20 participants) disability at six months in people with amyotrophic lateral
and a single-arm trial (42 participants) reported improvement in sclerosis/motor neuron disease (ALS/MND), but the available
neurological and lung function after repeated cell administration evidence is not sufficient to enable a clear conclusion regarding the
(Chen 2007). However, other reports did not support these clinical therapeutic efficacy and safety of cell-based therapy in ALS/MND.
observations (Chew 2007; Giordana 2010; Piepers 2010). Giordana
2010 reported postmortem findings from two people with ALS/ Implications for research
MND who received intracranial injection of foetal OESCs. OESC To date, there is no conclusive evidence that cell-based therapy
transplantation did not modify the neuropathology of ALS/MND alters the natural course of ALS/MND and prolongs survival, with
and there was an absence of axonal regeneration, neuronal currently available evidence limited by imprecision as a result of
differentiation and myelination. small sample size. There were significant shortcomings related to
the design of the available published studies. We found significant
Taken together, the findings in this review and previous studies variability between trials with regards to selection criteria, outcome
suggest that the potential use of autologous BM-MSC to may measures, and types of cells and methods of cell implantation.
slightly reduce the decline in motor function in people with ALS/ Moreover, these trials were generally underpowered to show any
MND (Karussis 2010; Oh 2015; Petrou 2015). clinical benefit. Prospective RCTs with larger sample size and
Apart from riluzole and non-invasive ventilation, current longer-term follow-up are urgently required to assess the clinical
management strategies have shown very limited effects on survival benefits of cell-based therapy including improvement in disease
in ALS/MND (Miller 2012; Radunovic 2013). The only RCT presented progression and quality of life and prolongation of survival in
in our review found no survival benefit of BM-MSC in people with people with ALS/MND. Importantly, data from well-designed trials
ALS/MND at six months (Oh 2018). This may be because of the might determine patient-, disease- and cell treatment-related
relative short follow-up period in Oh 2018. However, a long-term factors that could potentially influence the clinical outcomes of cell-
post hoc analysis of survival in Oh 2018 found no statistically based therapy.
significant difference in mean survival time in the MSC group (55 Questions remain as to the optimal cell source, phenotype and
(SE 4) months) compared to the control group (48 (SE 6) months) dose, as well as transplantation method and protocol that would
(log-rank test for survival P = 0.487). In contrast, two previous non- be key elements in designing an optimal cell-based therapy
RCTs showed that median survival in the cell-based therapy group programme for people with ALS/MND; these should be the major
was significantly longer than in the control group (66 months in goals of future research.
the CD133+ cell group versus 19 months in the control group; P
Informed decisions.

Combination of cellular therapy with standard therapy (riluzole) or neutrotrophic growth factors and combining mesenchymal
novel neuroprotective agents should also be explored to strengthen stem cell and neural stem cell transplantation).
the therapeutic efficacy and to find the best possible approach to
prevent or reverse the neurological deficit and to prolong survival ACKNOWLEDGEMENTS
of this otherwise debilitating and fatal condition.
The authors developed this review using a template originally
Studies to investigate the mechanisms of cellular neuroprotection developed by the Cochrane Airways Group, and adapted by
induced by cell implantation would be vital in developing an Cochrane Neuromuscular.
effective cell-based targeted therapy in ALS/MND. Future clinical
trials should consider the following factors. This project was supported by the National Institute for Health
Research (NIHR) via Cochrane Infrastructure funding to Cochrane
1. Improved trial designs and participant selection criteria, with Neuromuscular. The views and opinions expressed therein are
relevant clinical outcomes. those of the authors and do not necessarily reflect those of the
2. Long-term follow-up to establish long-term safety and durability Systematic Reviews Programme, NIHR, National Health Service
of the clinical benefit of cell-based therapy. or the Department of Health. Cochrane Neuromuscular is also
supported by the MRC Centre for Neuromuscular Disease and the
3. Standardisation of cell products used and cell implantation
Motor Neuron Disease Association.
protocols.
4. Detailed characterisation of cells used for implantation, The Cochrane Neuromuscular Information Specialist, Angela Gunn,
including viability and immunophenotype. advised the review authors on the search strategy.
5. In vivo cell tracking using advanced imaging technologies to
provide insight into the survival and migratory potential of The authors would like to acknowledge the Dean of Faculty
the grafted cells as well as safety issues such as aberrant of Medicine and Director of Hospital Canselor Tuanku Muhriz,
differentiation and migration. Universiti Kebangsaan Malaysia Medical Center for their support.
6. Postmortem pathological analysis of brain or spinal cord The review authors are grateful to the following peer reviewers
specimens from people with ALS/MND, to detect evidence of for their time and comments on this update: Dr Nikhil Sharma
neuroprotection or axonal regeneration of the diseased motor (National Hospital for Neurology, Queen Square, London and
neurons and evidence of aberrant differentiation or tumour University College London), Dr Sarah Nevitt (University of
formation. Liverpool), and also to the consumer peer reviewer, who wishes to
7. Use of novel cellular sources and treatment approaches remain anonymous.
(such as induced pluripotent stem cells, cell lines expressing

Informed decisions.

REFERENCES

References to studies included in this review References to studies excluded from this review
Gothelf 2017 {published data only} Gabr 2017 {published data only}
Aricha R, Cudkowicz M, Berry J, Windebank A, Staff N, Owegi M, Gabr H, Kishk N, Belal E, Aboelfotooh A, M E. Intrathecal
et al. In vivo modulation of neurotrophic and inflammatory autologous bone marrow derived mesenchymal stem cell
factors in the CSF of ALS patients treated with NurOwn (MSC therapy for amyotrophic lateral sclerosis. Cytotherapy 2017;19(5
NTF cells).. Cytotherapy 2017;19(5 Suppl 1):S199. [DOI: 10.1016/ Suppl 1):S199-200.
j.jcyt.2017.02.297; EMBASE: 621642066]
Karussis 2013 {published data only}
Aricha R, Kaspi H, Cudkowicz M, Berry J, Windebank A, * Karussis D, Petrou P, Offen D, Gothelf Y, Levy Y, Argov Z,
Staff N, et al. Modulation of CSF mirnas in ALS phase 2 study et al. Treatment of amyotrophic lateral sclerosis (ALS)
participants treated with MSC-NTF cells (NurOwn). Neurology with autologous differentiated mesenchymal stem cells:
2018;90(15 Suppl):S25.005. preliminary results of a phase I/II clinical trial in 12 patients.
Journal of Neurology 2013;260(Suppl 1):S22-3. [DOI: 10.1007/
* Gothelf Y, Cudkowicz M, Berry J, Windebank A, Staff N,
s00415-013-6924-0]
Owegi M, et al. Safety and efficacy of transplantation of NurOwn
(autologous mesenchymal stromal cells secreting neurotrophic Karussis D, Petrou P, Offen D, Gotkine M, Argov Z, Vaknin-
factors) in patients with ALS: a phase 2 randomized double Dembinsky A, et al. Interim analysis of 12 patients with
blind placebo controlled trial. Cryotherapy 2017;19(5 Suppl amyotrophic lateral sclerosis (ALS) treated with autologous
1):S23. [EMBASE: 621642188] differentiated mesenchymal stem cells: preliminary data of
a Phase I/II clinical trial. Neurology 2013;80(19):e202-3. [DOI:
Kern R, Cudkowicz M, Berry J, Windebank A, Staff N, Owegi M,
10.1212/WNL.0b013e3182924c84]
et al. NurOwn phase 2 ALS trial: ALSFRS-R improvement
is reflected in subscale domains. Neurology 2018;90(15 Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, et
Suppl):Abstract No:S38.002. al. Safety and clinical effects of mesenchymal stem cells
secreting neurotrophic factor transplantation in patients with
NCT02017912. A phase 2, randomised, double blind, placebo
amyotrophic lateral sclerosis: results of phase 1/2 and 2a
controlled multicenter study to evaluate safety and efficacy
clinical trials. JAMA Neurology 2016;73(3):337-44. [DOI: 10.1001/
of transplantation of autologous mesenchymal stem cells
jamaneurol.2015.4321; PUBMED: 26751635]
secreting neurotrophic factors (MSC-NTF) in patients with ALS.
clinicaltrials.gov/ct2/show/study/NCT02017912 (first received Mazzini 2015 {published data only}
23 December 2013).
* Mazzini L, Gelati M, Profico DC, Sgaravizzi G, Projetti Pensi M,
Oh 2018 {published data only} Muzi G, et al. Human neural stem cell transplantation in ALS:
initial results from a phase I trial. Journal of Translational
Kim SH. Phase I/II trials of autologous BM derived stem cell
Medicine 2015;13:17. [DOI: 10.1186/s12967-014-0371-2;
therapy in ALS. Clinical Neurology 2016;56:S228. [EMBASE:
PUBMED: 25889343]
615586834]
Mazzini L, Gelati M, Soraru G, Profico D, Muzi G, Ricciolini C, et
Kim SH, Oh K-W, Kwon M-S, Moon CM, Noh M-Y, Kim HY, et al. A
al. Data from a completed phase I clinical trial with intraspinal
phase 2 study for safety and efficacy evaluation of treatment
injection of neural stem cells in amyotrophic lateral sclerosis.
of amyotrophic lateral sclerosis using autologous bone-
Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
marrow-derived stromal cell. Amyotrophic Lateral Sclerosis and
2016;17(Suppl 1):243.
Frontotemporal Degeneration 2015;16(Suppl 1):53. [EMBASE:
72104358] Nabavi 2019 {published data only}
NCT01363401. Safety and efficacy study of autologous bone Nabavi SM, Arab L, Jarooghi N, Bolurieh T, Abbasi F, Mardpour S,
marrow derived stem cell treatment in amyotrophic lateral et al. Safety, feasibility of intravenous and intrathecal injection
sclerosis [An open-label, phase I/II trial for safety and efficacy of autologous bone marrow derived mesenchymal stromal cells
study of autologous bone marrow derived stem cell treatment in patients with amyotrophic lateral sclerosis: an open label
in amyotrophic lateral sclerosis]. clinicaltrials.gov/ct2/show/ phase I clinical trial. Cell Journal 2019;20(4):592-8. [PUBMED:
NCT01363401 (first received 1 June 2011). [CTG: NCT01363401] 30124008]
* Oh KW, Noh MY, Kwon MS, Kim HY, Oh SI, Park J, et al. Petrou 2015 {published data only}
Repeated intrathecal mesenchymal stem cells for amyotrophic Gothelf Y, Petrou P, Gotkine M, Vaknin-Dembinsky A, Levy Y,
lateral sclerosis. Annals of Neurology 2018;84(3):361-73. Offen D, et al. Update on clinical trials with autologous
[PUBMED: 30048006] bone marrow-derived mesenchymal stem cells secreting
neurotrophic factors (MSC-NTF) in patients with amyotrophic
lateral sclerosis (ALS). Cytotherapy 2015;17(6 Suppl):S38-9. [DOI:
10.1016/j.jcyt.2015.03.434]

Informed decisions.

Karussis D, Petrou P, Offen D, Argov Z, Gotkine M, Levi Y, et al. infusion of autologous bone marrow stem cells in patients with
Analysis of patients with amyotrophic lateral sclerosis (ALS) amyotrophic lateral sclerosis.]. clinicaltrials.gov/ct2/show/
treated with autologous differentiated mesenchymal stem cells: NCT02286011 (first received 7 November 2014).
a phase I/II and IIA clinical trial. Amyotrophic Lateral Sclerosis
and Frontotemporal Degeneration 2013;14(Suppl 2):48. [DOI: NCT02290886 {published data only}
10.3109/21678421.2013.838413/078] NCT02290886. A multicenter phase I/II clinical trial to evaluate
safety of mesenchymal stem cell in patients with amyotrophic
Karussis D, Petrou P, Offen D, Argov Z, Goudkin M, Levi Y, et al. sclerosis lateral [Clinical trial phase I/II, randomised, controlled
Analysis of patients with amyotrophic lateral sclerosis (ALS) with placebo, triple blind to evaluate safety, and indications
treated with autologous differentiated mesenchymal stem of efficiency of the intravenous administration of the therapy
cells: A phase I/II and IIa clinical trial. Journal of Neurology with 3 doses of MSC in patients with ALS moderated to severe].
2014;261(Suppl 1):S47-8. [DOI: 10.1007/s00415-013-6924-0] clinicaltrials.gov/ct2/show/study/NCT02290886 (first received
14 November 2014).
Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, et
al. Safety and clinical effects of mesenchymal stem cells NCT03280056 {published data only}
secreting neurotrophic factor transplantation in patients with
NCT03280056. Safety and efficacy of repeated administrations
amyotrophic lateral sclerosis: results of phase 1/2 and 2a
of NurOwn® in ALS patients [A phase 3, randomized double-
clinical trials. JAMA Neurology 2016;73(3):337-44. [DOI: 10.1001/
blind, placebo-controlled multicenter study to evaluate efficacy
jamaneurol.2015.4321; PUBMED: 26751635]
and safety of repeated administration of NurOwn® (autologous
* Petrou P, Gotkine M, Gothelf Y, Levy Y, Offen D, Vaknin- mesenchymal stem cells secreting neurotrophic factors) in
Dembinsky A, et al. Autologous transplantation of mesenchymal participants with ALS]. clinicaltrials.gov/ct2/show/study/
stem cells secreting neurotrophic factors (NurownTM) in NCT03280056 (first received 12 September 2017). [BCT-002-US]
ALS: results of a phase 2 clinical trial. Neurology 2015;84(14

Suppl):P2.059.
Additional references
Abdul 2018
References to ongoing studies
Abdul Wahid SF, Ismail NA, Wan Jamaludin WF, Muhamad NA,
NCT01254539 {published data only} Abdul Hamid MKA, Harunarashid H, et al. Autologous cells
Henriquez K, De Mingo Casado P, Saez V, Izura V. Cellular derived from different sources and administered using different
therapy in amyotrophic lateral sclerosis. Preliminary results of a regimens for 'no-option' critical lower limb ischaemia patients.
phase I/II clinical trial. Clinical Neurophysiology 2014;125(Suppl Cochrane Database of Systematic Reviews 2018, Issue 8. [DOI:
1):S194-5. [EMBASE: 71541589] 10.1002/14651858.CD010747.pub2; PUBMED: 30155883]
Iniesta F, Gomez-Espuch J, Blanquer M, Perez-Espejo MA, Abe 2014

Garcia-Santos JM, Ruiz-Lopez FJ, et al. Bone marrow Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, et al.
mononuclear cell therapy for amyotrophic lateral sclerosis. Edaravone ALS Study Group. Confirmatory double-blind,
Preliminary results of a randomised, double-blind, stratified parallel-group, placebo-controlled study of efficacy and
controlled, parallel group phase I-II clinical trial. Human Gene safety of edaravone (MCI-186) in amyotrophic lateral
Therapy 2013;24(12):A49. [DOI: 10.1089/hum.2013.2513] sclerosis patients. Amyotrophic Lateral Sclerosis and
Frontotemporal Degeneration 2014;15(7-8):610-7. [DOI:
* NCT01254539. Phase I/II clinical trial on the use of autologous 10.3109/21678421.2014.959024]
bone marrow stem cells in amyotrophic lateral sclerosis
(Extension CMN/ELA). clinicaltrials.gov/ct2/show/NCT01254539 Baek 2012
(accessed September 2015). Baek W, Kim YS, Koh SH, Lim SW, Kim HY, Yi HJ, et al. Stem cell
transplantation into the intraventricular space via an Ommaya
NCT02286011 {published data only}
reservoir in a patient with amyotrophic lateral sclerosis.
Cano R, Martin C, Pastore C, Blanquer M, Iniesta P, Gomez- Journal of Neurosurgical Sciences 2012;56(3):261-3. [; PUBMED:
Espuch J, et al. Phase I/II clinical trial of intramuscular 22854595]
implantation of autologous bone marrow stem cells in
amyotrophic lateral sclerosis patients. Basic & Clinical Bensimon 1994
Pharmacology & Toxicology 2012;111(Supp s1):40: Abstract no: Bensimon G, Lacomblez L, Meininger V. A controlled trial of
P102. riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study
Group. New England Journal of Medicine 1994;330(9):585-91.
EUCTR2011-004801-25-ES. A phase I/II clinical trial of the bone
[PUBMED: 8302340]
marrow's autologous stem cells in patients with amyotrophic
lateral sclerosis. www.clinicaltrialsregister.eu/ctr-search/ Bernardo 2007
trial/2011-004801-25/ES (accessed September 2015).
Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA,
* NCT02286011. Intramuscular infusion of autologous bone Moretta A, et al. Human bone marrow derived mesenchymal
marrow stem cells in patients with amyotrophic lateral stem cells do not undergo transformation after long-term
sclerosis (TCIM/ELA) [Phase I clinical trial on intramuscular in vitro culture and do not exhibit telomere maintenance

Informed decisions.

mechanisms. Cancer Research 2007;67(19):9142-9. [PUBMED: Chen 1996

17909019] Chen R, Grand'Maison F, Strong MJ, Ramsay DA, Bolton CF.
Motor neuron disease presenting as acute respiratory failure:
Black 2001
a clinical and pathological study. Journal of Neurology,
Black IB, Woodbury D. Adult rat and human bone marrow Neurosurgery, and Psychiatry 1996;60(4):455-8. [PUBMED:
stromal stem cells differentiate into neurons. Blood Cells, 8774419]
Molecules & Diseases 2001;27(3):632-6. [PUBMED: 11482877]
Chen 2007
Blanquer 2012
Chen L, Huang H, Zhang J, Zhang F, Liu Y, Xi H, et al. Short-term
Blanquer M, Moraleda JM, Iniesta F, Gomez-Espuch J, Meca- outcome of olfactory ensheathing cells transplantation for
Lallana J, Villaverde R, et al. Neurotrophic bone marrow treatment of amyotrophic lateral sclerosis. Zhongguo Xiu Fu
cellular nests prevent spinal motoneuron degeneration in Chong Jian Wai Ke za Zhi [Chinese Journal of Reparative and
amyotrophic lateral sclerosis patients: a pilot safety study. Stem Reconstructive Surgery] 2007;21(9):961-6. [PUBMED: 17933231]
Cells 2012;30(6):1277-85. [DOI: 10.1002/stem.1080; PUBMED:
22415951] Chen 2008
Chen Y, Shao JZ, Xiang LX, Dong XJ, Zhang GR. Mesenchymal
Bourke 2006
stem cells: a promising candidate in regenerative medicine.
Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, International Journal of Biochemistry and Molecular Biology
Gibson GJ. Effects of non-invasive ventilation on survival and 2008;40(5):815-20. [DOI: 10.1016/j.biocel.2008.01.007; PUBMED:
quality of life in patients with amyotrophic lateral sclerosis: a 18295530]
randomised controlled trial. Lancet Neurology 2006;5(2):140-7.
[DOI: 10.1016/S1474-4422(05)70326-4; PUBMED: 16426990 ] Chew 2007
Chew S, Khandji AG, Montes J, Mitsumoto H, Gordon PH.
Brooks 2000
Olfactory ensheathing glia injections in Beijing: misleading
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation patients with ALS. Amyotrophic Lateral Sclerosis 2007;8(5):314-6.
of Neurology Research Group on Motor Neuron Diseases. [PUBMED: 17917850]
El Escorial revisited: revised criteria for the diagnosis of
amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis Chio 2011
and Other Motor Neuron Disorders 2000;1(5):293-9. [PUBMED: Chio A, Mora G, La Bella V, Caponnetto C, Mancardi G,
11464847] Sabatelli M, et al. Repeated courses of granulocyte colony-
stimulating factor in amyotrophic lateral sclerosis: clinical and
Campbell 2001
biological results from a prospective multicenter study. Muscle
Campbell MK, Mollison J, Grimshaw JM. Cluster trials & Nerve 2011;43(2):189-95. [; DOI: 10.3109/14653240903300682;
in implementation research: estimation of intracluster PUBMED: 21254083]
correlation coefficients and sample size. Statistics in Medicine
2001;20(3):391-9. [PUBMED: 11180309] Cruz 2018
Cruz MP. Edaravone (Radicava): a novel neuroprotective agent
Caroscio 1987
for the treatment of amyotrophic lateral sclerosis. P & T : a Peer-
Caroscio JT, Mulvihill MN, Sterling R, Abrams B. Amyotrophic reviewed Journal for Formulary Management 2018;43(1):25-8.
lateral sclerosis. Its natural history. Neurologic Clinics [PUBMED: 29290672]
1987;5(1):1-8. [PUBMED: 3561382]
Deda 2009
Cashman 2008
Deda H, Inci MC, Kurekci AE, Sav A, Kayihan K, Ozgun E,
Cashman N, Tan LY, Krieger C, Madler B, Mackay A, Mackenzie I, et al. Treatment of amyotrophic lateral sclerosis patients
et al. Pilot study of granulocyte colony stimulating factor (G- by autologous bone marrow-derived hematopoietic
CSF)-mobilized peripheral blood stem cells in amyotrophic stem cell transplantation: a 1-year follow-up. Cytotherapy
lateral sclerosis (ALS). Muscle & Nerve 2008;37(5):620-5. [; DOI: 2009;11(1):18-25. [; PUBMED: 19012065]
10.1002/mus.20951; PUBMED: 18335482]
Deeks 2011
Castrillo-Viguera 2010
Deeks JJ, Higgins JP, Altman DG, on behalf of the Cochrane
Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Statistical Methods Group. Chapter 10: Analysing data
Cudkowicz ME. Clinical significance in the change of decline in and undertaking meta-analyses. In: Higgins JP, Green S,
ALSFRS-R. Amyotrophic Lateral Sclerosis 2010;11(1-2):178-80. editor(s). Cochrane Handbook for Systematic Reviews of
[PUBMED: 19634063] Interventions Version 5.1.0 (updated March 2011). The Cochrane
Collaboration, 2011. Available from handbook.cochrane.org.
Cedarbaum 1999
Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, del Aguila 2003
Thurmond B, et al. The ALSFRS-R: a revised ALS functional del Aguila MA, Longstreth WT Jr, McGuire V, Koepsell TD,
rating scale that incorporates assessments of respiratory van Belle G. Prognosis in amyotrophic lateral sclerosis: a
function. BDNF ALS Study Group (Phase III). Journal of the population-based study. Neurology 2003;60(5):813-9. [PUBMED:
Neurological Sciences 1999;169(1-2):13-21. [PUBMED: 10540002] 12629239]

Informed decisions.

Deng 2011 for studying neuroprotection and neurodegeneration.

Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Molecular Neurobiology 2010;42(1):97-102. [DOI: 10.1007/
et al. Mutations in UBQLN2 cause dominant X-linked s12035-010-8136-2; PUBMED: 20431962]
juvenile and adult-onset ALS and ALS/dementia. Nature
Higgins 2011a
2011;477(7363):211-5. [DOI: 10.1038/nature10353]
Higgins JP, Altman DG, Sterne JA. Chapter 8: Assessing
Escorcio-Bezerra 2016 risk of bias in included studies. In: Higgins JP, Green S,
Escorcio-Bezerra ML, Abrahao A, de Castro I, Chieia MA, editor(s). Cochrane Handbook for Systematic Reviews of
de Azevedo LA, Pinheiro DS, et al. MUNIX: reproducibility Interventions Version 5.1.0 (updated March 2011). The Cochrane
and clinical correlations in amyotrophic lateral sclerosis. Collaboration, 2011. Available from handbook.cochrane.org.
Clinical Neurophysiology 2016;127(9):2979-84. [DOI: 10.1016/
Higgins 2011b
j.clinph.2016.06.011; PUBMED: 27458836]
McKenzie JE, Brennan SE. Chapter 12: Synthesizing and
Feldman 2014 presenting findings using other methods. In: Higgins JP, Green
Feldman EL, Boulis NM, Hur J, Johe K, Rutkove SB, Federici T, et S, editor(s). Cochrane Handbook for Systematic Reviews of
al. Intraspinal neural stem cell transplantation in amyotrophic Interventions Version 5.1.0 (updated March 2011). The Cochrane
lateral sclerosis: phase 1 trial outcomes. Annals of Neurology Collaboration, 2011. Available from handbook.cochrane.org.
2014;75(3):363-73. [PUBMED: 24510776]
Huang 2008
Gawel 2016 Huang H, Chen L, Xi H, Wang H, Zhang J, Zhang F, et al. Fetal
Gawel M, Zalewska E, Lipowska M, Kostera-Pruszczyk A, Szmidt- olfactory ensheathing cells transplantation in amyotrophic
Salkowska E, Kaminska A. Motor unit number estimation lateral sclerosis patients: a controlled pilot study. Clinical
as a complementary test to routine electromyography in Transplantation 2008;22(6):710-8. [PUBMED: 18673377]
the diagnosis of amyotrophic lateral sclerosis. Journal of
Jenkinson 2000
Electromyography and Kinesiology 2016;26:60-5. [DOI: 10.1016/
j.jelekin.2015.11.001] Jenkinson C, Levvy G, Fitzpatrick R, Garratt A. The amyotrophic
lateral sclerosis assessment questionnaire (ALSAQ-40):
Giordana 2010 tests of data quality, score reliability and response rate in
Giordana MT, Grifoni S, Votta B, Magistrello M, Vercellino M, a survey of patients. Journal of the Neurological Sciences
Pellerino A, et al. Neuropathology of olfactory ensheathing 2000;180(1-2):94-100. [PUBMED: 11090872]]
cell transplantation into the brain of two amyotrophic lateral
Jenkinson 2007
sclerosis (ALS) patients. Brain Pathology (Zurich, Switzerland)
2010;20(4):730-7. [DOI: 10.1111/j.1750-3639.2009.00353.x; Jenkinson C, Fitzpatrick R, Swash M, Jones G. Comparison
PUBMED: 19919605] of the 40-item Amyotrophic Lateral Sclerosis Assessment
Questionnaire (ALSAQ-40) with a short-form five-item version
Goodall 2006 (ALSAQ-5) in a longitudinal survey. Clinical Rehabilitation
Goodall EF, Morrison KE. Amyotrophic lateral sclerosis 2007;21(3):266-72. [DOI: 10.1177/0269215506071123; PUBMED:
(motor neuron disease): proposed mechanisms and 17329284]
pathways to treatment. Expert Reviews in Molecular Medicine
Jeong 2015
2006;8(11):1-22. [PUBMED: 16723044]
Jeong H, Yim HW, Cho Y, Kim HB, Oh IH, Jeong S. Systematic
Goutman 2015 review and meta-analysis of efficacy and safety of stem cell
Goutman SA, Chen KS, Feldman EL. Recent advances and therapy in amyotrophic lateral sclerosis. Cytotherapy 2015;17(6
the future of stem cell therapies in amyotrophic lateral Suppl):S66. [DOI: 10.1016/j.jcyt.2015.03.530]
sclerosis. Neurotherapeutics 2015;12(2):428-48. [DOI: 10.1007/
Jiang 2002
s13311-015-0339-9; PUBMED: 25776222]
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD,
Gowing 2011 Ortiz-Gonzalez XR, et al. Pluripotency of mesenchymal stem
Gowing G, Svendsen CN. Stem cell transplantation for cells derived from adult marrow. Nature 2002;418(6893):41-9.
motor neuron disease: current approaches and future [PUBMED: 12077603]
perspectives. Neurotherapeutics 2011;8(4):591-606. [DOI:
Karussis 2010
10.1007/s13311-011-0068-7; PUBMED: 21904789]
Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-
GRADEpro 2018 [Computer program] Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological
GRADE Working Group, McMaster University. GRADEpro GDT. effects of mesenchymal stem cell transplantation in patients
Version 3.6. Hamilton (ON): GRADE Working Group, McMaster with multiple sclerosis and amyotrophic lateral sclerosis.
University, 2018. Archives of Neurology 2010;67(10):1187-94. [DOI: 10.1001/
archneurol.2010.248; PUBMED: 20937945]
Hardingham 2010
Hardingham GE, Patani R, Baxter P, Wyllie DJ, Chandran S.
Human embryonic stem cell-derived neurons as a tool

Informed decisions.

Kim 2002 Mazzini 2012

Kim BJ, Seo JH, Bubien JK, Oh YS. Differentiation of adult Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S,
bone marrow stem cells into neuroprogenitor cells in vitro. et al. Mesenchymal stromal cell transplantation in amyotrophic
Neuroreport 2002;13(9):1185-8. [PUBMED: 12151766] lateral sclerosis: a long-term safety study. Cytotherapy
2012;14(1):56-60. [DOI: 10.3109/14653249.2011.613929;
Liu 2000 PUBMED: 21954839]
Liu S, Qu Y, Stewart TJ, Howard MJ, Chakrabortty S,
Holekamp TF, et al. Embryonic stem cells differentiate into McDonald 1999
oligodendrocytes and myelinate in culture and after spinal McDonald JW, Liu XZ, Qu Y, Liu S, Mickey SK, Turetsky D, et al.
cord transplantation. Proceedings of the National Academy of Transplanted embryonic stem cells survive, differentiate and
Sciences of the United States of America 2000;97(11):6126-31. promote recovery in injured rat spinal cord. Nature Medicine
[PUBMED: 10823956] 1999;5(12):1410-2. [PUBMED: 10581084]
Logroscino 2005 Miller 2012

Logroscino G, Beghi E, Zoccolella S, Palagano R, Fraddosio A, Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic
Simone I, et al. Incidence of amyotrophic lateral sclerosis in lateral sclerosis (ALS)/motor neuron disease (MND).
southern Italy: a population based study. Journal of Neurology, Cochrane Database of Systematic Reviews 2012, Issue 3. [DOI:
Neurosurgery, and Psychiatry 2005;76(8):1094-8. [PUBMED: 10.1002/14651858.CD001447.pub3]
16024886]
Moher 2009
Logroscino 2008 Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA
Logroscino G, Traynor BJ, Hardiman O, Chio A, Couratier P, Group. Preferred Reporting Items for Systematic Reviews
Mitchell JD, et al. Descriptive epidemiology of amyotrophic and Meta-Analyses: the PRISMA statement. PLoS Medicine
lateral sclerosis: new evidence and unsolved issues. Journal 2009;6(7):e1000097. [DOI: 10.1371/journal.pmed1000097]
of Neurology, Neurosurgery, and Psychiatry 2008;79(1):6-11.
[PUBMED: 18079297] Moura 2016
Moura MC, Novaes MR, Zago YS, Eduardo EJ, Casulari LA.
Lunn 2014 Efficacy of stem cell therapy in amyotrophic lateral sclerosis:
Lunn JS, Sakowski SA, Feldman EL. Concise review: stem cell a systematic review and meta-analysis. Journal of Clinical
therapies for amyotrophic lateral sclerosis: recent advances Medicine Research 2016;8(4):317-24. [PUBMED: 26985252]
and prospects for the future. Stem Cells (Dayton, Ohio)
2014;32(5):1099-109. [DOI: 10.1002/stem.1628; PUBMED: Murray 2004
24448926] Murray B, Mitsumoto H. Disorders of upper and lower motor
neurons. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J
Martinez 2009 editor(s). Neurology in Clinical Practice. 4th Edition. Vol. 1,
Martinez HR, Gonzalez-Garza MT, Moreno-Cuevas JE, Caro E, Philadelphia (PA): Butterworth-Heinemann, 2004:2223-65.
Gutierrez-Jimenez E, Segura JJ. Stem-cell transplantation
into the frontal motor cortex in amyotrophic lateral Nefussy 2010
sclerosis patients. Cytotherapy 2009;11(1):26-34. [; DOI: Nefussy B, Artamonov I, Deutsch V, Naparstek E, Nagler A,
10.1080/14653240802644651; PUBMED: 19191058] Drory VE. Recombinant human granulocyte-colony stimulating
factor administration for treating amyotrophic lateral sclerosis:
Martinez 2012 a pilot study. Amyotrophic Lateral Sclerosis 2010;11(1-2):187-93.
Martinez HR, Molina-Lopez JF, Gonzalez-Garza MT, Moreno- [; DOI: 10.3109/17482960902933809; PUBMED: 19449238]
Cuevas JE, Caro-Osorio E, Gil-Valadez A, et al. Stem cell
transplantation in amyotrophic lateral sclerosis patients: Oakes 2017
methodological approach, safety, and feasibility. Cell Oakes JA, Davies MC, Collins MO. TBK1: a new player in ALS
Transplantation 2012;21(9):1899-907. [; PUBMED: 23356668] linking autophagy and neuroinflammation. Molecular Brain
2017;10(1):5. [DOI: 10.1186/s13041-017-0287-x]
Mazzini 2003
Mazzini L, Fagioli F, Boccaletti R, Mareschi K, Oliveri G, Olivieri C, Oh 2015
et al. Stem cell therapy in amyotrophic lateral sclerosis: a Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, et al. Phase I
methodological approach in humans. Amyotrophic Lateral trial of repeated intrathecal autologous bone marrow-derived
Sclerosis and Other Motor Neuron Disorders 2003;4(3):158-61. [; mesenchymal stromal cells in amyotrophic lateral sclerosis.
PUBMED: 13129802] Stem Cells Translational Medicine 2015;4(6):590-7. [; DOI:
10.5966/sctm.2014-0212; PUBMED: 25934946]
Mazzini 2006
Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Piepers 2010
Boccaletti R, et al. Autologous mesenchymal stem cells: clinical Piepers S, van den Berg LH. No benefits from experimental
applications in amyotrophic lateral sclerosis. Neurological treatment with olfactory ensheathing cells in patients with
Research 2006;28(5):523-6. [PUBMED: 16808883] ALS. Amyotrophic Lateral Sclerosis 2010;11(3):328-30. [DOI:
10.3109/17482961003663555; PUBMED: 20433414]

Informed decisions.

Prabhakar 2012 Terada 2002

Prabhakar S, Marwaha N, Lal V, Sharma RR, Rajan R, Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y,
Khandelwal N. Autologous bone marrow-derived stem cells et al. Bone marrow cells adopt the phenotype of other cells
in amyotrophic lateral sclerosis: a pilot study. Neurology India by spontaneous cell fusion. Nature 2002;416(6880):542-5.
2012;60(5):465-9. [; PUBMED: 23135021] [PUBMED: 11932747]
Rabin 1999 Thonhoff 2009

Rabin BA, Borchelt DR. Motor neuron disease. In: Koliatsos VE, Thonhoff JR, Ojeda L, Wu P. Stem cell-derived motor neurons:
Ratan RR editor(s). Cell Death and Diseases of the Nervous applications and challenges in amyotrophic lateral sclerosis.
System. New York (NY): Springer Science + Business Media, Current Stem Cell Research & Therapy 2009;4(3):178-99.
1999:429-43. [PUBMED: 19492980]
Rabin 2001 Turner 2003

Rabin R, de Charro F. EQ-5D: a measure of health status from the Turner MR, Parton MJ, Shaw CE, Leigh PN, Al-Chalabi A.
EuroQol Group. Annals of Medicine 2001;33(5):337-43. [PUBMED: Prolonged survival in motor neuron disease: a descriptive
11491192] study of the King's database 1990-2002. Journal of Neurology,
Neurosurgery, and Psychiatry 2003;74(7):995-7. [PUBMED:
Radunovic 2013 12810805]
Radunovic A, Annane D, Rafiq MK, Mustfa N. Mechanical
ventilation for amyotrophic lateral sclerosis/motor neuron Uccelli 2008
disease. Cochrane Database of Systematic Reviews 2013, Issue 3. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health
[DOI: 10.1002/14651858.CD004427.pub3; PUBMED: 23543531] and disease. Nature Reviews Immunology 2008;8(9):726-36.
[DOI: 10.1038/nri2395; PUBMED: 19172693]
Renton 2014
Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic Ware 1992
lateral sclerosis genetics. Nature Neuroscience 2014;17(1):17-23. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health
[DOI: 10.1038/nn.3584; PUBMED: 24369373] survey (SF-36). I. Conceptual framework and item selection.
Medical Care 1992;30(6):473-83. [PUBMED: 1593914]
Review Manager 2014 [Computer program]
Nordic Cochrane Centre, The Cochrane Collaboration. Review Woodbury 2000
Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and
Cochrane Centre, The Cochrane Collaboration, 2014. human bone marrow stromal cells differentiate into neurons.
Journal of Neuroscience Research 2000;61(4):364-70. [PUBMED:
Sanchez-Ramos 2000 10931522]
Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C,
Stedeford T, Willing A, et al. Adult bone marrow stromal cells Writing Group 2017
differentiate into neural cells in vitro. Experimental Neurology Writing Group, Edaravone (MCI-186) ALS 19 Study Group.
2000;164(2):247-56. [PUBMED: 10915564] Safety and efficacy of edaravone in well defined patients with
amyotrophic lateral sclerosis: a randomised, double-blind,
Sharma 2015 placebo-controlled trial. Lancet Neurology 2017;16(7):505-12.
Sharma AK, Sane HM, Paranjape AA, Gokulchandran N, [DOI: 10.1016/S1474-4422(17)30115-1]
Nagrajan A, D'sa M, et al. The effect of autologous bone marrow
mononuclear cell transplantation on the survival duration
in amyotrophic lateral sclerosis – a retrospective controlled References to other published versions of this review
study. American Journal of Stem Cells 2015;4(1):50-65. [PUBMED: Abdul Wahid 2015
25973331]
Abdul Wahid SF, Law ZK, Lai NM, Ismail NA, Azman Ali R. Cell-
Shaw 2005 based therapies for amyotrophic lateral sclerosis/motor neuron
disease. Cochrane Database of Systematic Reviews 2015, Issue 6.
Shaw PJ. Molecular and cellular pathways of neurodegeneration
[DOI: 10.1002/14651858.CD011742]
in motor neurone disease. Journal of Neurology, Neurosurgery,
and Psychiatry 2005;76(8):1046-57. [PUBMED: 16024877] Abdul-Wahid 2016
Stein 2016 Abdul Wahid SF, Law ZK, Lai NM, Ismail NA, Azman Ali R. Cell-
based therapies for amyotrophic lateral sclerosis/motor neuron
Stein F, Kobor I, Bogdahn U, Schulte-Mattler WJ. Toward the
disease. Cochrane Database of Systematic Reviews 2016, Issue
validation of a new method (MUNIX) for motor unit number
11. [DOI: 10.1002/14651858.CD011742.pub2]
assessment. Journal of Electromyography and Kinesiology
2016;27:73-7. [DOI: 10.1016/j.jelekin.2016.02.001; PUBMED:
26930263 ] * Indicates the major publication for the study


Informed decisions.

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Gothelf 2017
Methods Study design: phase 2, randomised, double-blind, placebo-controlled, multicentre study
Participants Country: US
Number of participants: 48
Mean age: 51.1 years
Sex: 35 men, 13 women
Inclusion criteria
1. Men and women aged 18–75 years, inclusive

2. ALS/MND diagnosed as possible, laboratory-supported probable, probable or definite, as defined by
revised El Escorial criteria
3. Disease onset, as defined by first reported occurrence of symptomatic weakness, spasticity or bulbar
symptoms, of ˃ 12 months and ≤ 24 months
4. Current disease symptoms must have included limb weakness
5. ALSFRS-R ≥ 30 at the screening visit
6. Upright slow vital capacity measure ≥ 65% of predicted for gender, height and age at the screening
visit
7. Participants must have been taking a stable dose of riluzole for at least 30 days prior to enrolment or
not be taking riluzole, and not have been on it for ≥ 30 days prior to enrolment (riluzole-naive partic-
ipants permitted in the study)
8. Capable of providing informed consent and willing and able to follow study procedures, including
willingness to undergo lumbar puncture
9. Geographic accessibility to the study site and willingness and ability to comply with follow-up
10.Women of child-bearing potential must have agreed not to become pregnant for the duration of the
study. Women must have been willing to consistently use 2 forms of contraceptive therapy throughout
the course of the trial, and undergo a pregnancy test 1 week before BM aspiration. Men must have
been willing to consistently use 2 forms of contraceptive if their partners were of child-bearing age
11.Citizen or permanent resident of the US
Exclusion criteria
1. Prior stem cell therapy of any type

2. Inability to lie flat for the duration of intrathecal cell transplantation or BM biopsy, or inability to tol-
erate study procedures for any other reason
3. History of autoimmune disease (excluding thyroid disease), myelodysplastic or myeloproliferative
disorder, leukaemia or lymphoma, whole body irradiation, hip fracture or severe scoliosis
4. Any unstable clinically significant medical condition other than ALS/MND (e.g. myocardial infarction,
angina pectoris or congestive heart failure within 6 months of baseline), treatment with anticoagu-
lants that, in the opinion of the investigator, would compromise the safety of participants
5. Any history of malignancy including any malignancy affecting the central nervous system and
melanoma, within the previous 5 years, with the exception of localised skin cancers (with no evidence
of metastasis, significant invasion or re-occurrence within 3 years of baseline)
6. Serum AST or ALT values > 3 times the upper normal limit
7. Serum creatinine value > 2 times the upper normal limit
8. Positive test for HBV, HCV or HIV
9. Current use of immunosuppressant medication or use of such medication within 4 weeks of screening
visit
10.History of acquired or inherited immune deficiency syndrome

Informed decisions.

Gothelf 2017 (Continued)
11.Exposure to any other experimental agent (off-label use or investigational), or participation in a clin-
ical trial within 30 days prior to screening visit
12.Use of non-invasive ventilation, diaphragm pacing system or invasive ventilation (tracheostomy)
13.History of either substance abuse within the past year or unstable psychiatric disease according to
investigators' judgement
14.Placement or usage of feeding tube
15.Pregnant or currently breastfeeding
Interventions Autologous MSC-NTF cells; cell dose not mentioned
Placebo
Outcomes Primary outcome
1. Number of participants with adverse events
Secondary outcomes
1. Change in ALSFRS slopes from the pretransplantation period to the post-transplantation period be-
tween the treatment and placebo groups for 24 weeks after transplantation
2. Change in slow vital capacity slopes from the pretransplantation period to the post-transplantation
period between the treatment and placebo groups for 24 weeks after transplantation
Funding Funded Brainstorm-Cell Therapeutics
Conflicts of interest Not clearly stated.
Notes Information obtained from a combination of 2 oral presentation abstracts and a trial registry record.
Repeated attempts to contact study authors for outcome data were unsuccessful.
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Quote: "This Phase 2 multicenter double blind, placebo-controlled trial en-
tion (selection bias) rolled 48 participants with ALS randomized 3:1 (active:placebo)."
Methods of sequence generation not stated.
Allocation concealment Unclear risk No information in the abstracts and trial records to enable a meaningful as-
(selection bias) sessment of the independence of sequence generation and allocation.
Blinding of participants Unclear risk Quote: "double blind, placebo-controlled."

and personnel (perfor-
mance bias) However, there was no detailed description of the blinding mechanism.
All outcomes
Blinding of outcome as- Unclear risk It was unclear whether the outcome assessor was blinded for the major out-
sessment (detection bias) comes, such as adverse effects and improvement in ALSFRS-R slope of decline
All outcomes in function.
Incomplete outcome data Unclear risk The authors stated that 48 participants were recruited, but it was unclear how
(attrition bias) many participants were included in the analysis, as the results were presented
All outcomes only in percentages.
Selective reporting (re- High risk It appeared that the major outcomes appropriate for a phase 2 trial, namely
porting bias) adverse effects and clinical improvements, were reported. However, the re-
ports provided insufficient detail, as the authors only reported the results in

Informed decisions.

Gothelf 2017 (Continued)
terms of percentages and P values, and did not provide the number of partici-
pants analysed and the absolute number of participants with events.
Other bias Unclear risk The oral presentation abstracts and the trial records provided insufficient de-
tail for assessment of other biases.

Oh 2018
Methods Study design: parallel-group, randomised, controlled phase 2 trial
Participants Country: Republic of Korea
Number of participants: 64
Mean age: 53.3 years
Sex: 33 men, 31 women
Study dates: enrolled between December 2011 and November 2012 and followed up until July 2013
Inclusion criteria
1. People aged 25–75 years diagnosed with clinically probable or definite ALS/MND according to the re-
vised El Escorial criteria.
2. ALSFRS-R score 31–46
3. Stable riluzole treatment (50 mg, twice daily) for at least 3 months before screening
4. Disease duration < 5 years after the onset of first symptoms
Exclusion criteria
1. Participation in other clinical trials within the past 12 months

2. FVC < 40% of the predicted value
3. Presence of any comorbidity that might interfere with the outcome
4. Tracheostomy or non-invasive ventilation
5. Any haemorrhagic tendency
6. Administration of any drug that could affect the BM
Follow-up period: 6 months
Interventions Intrathecal BM-MSCs plus riluzole (33 participants)
Riluzole alone (control group; 31 participants)
Outcomes Primary outcomes
1. Adverse effects, any or serious from baseline (0 month) to month 6

2. Difference in changes of ALSFRS-R from baseline (0 month) to months 4 and 6
Secondary outcomes
1. Change in Appel ALS Rating Scale from baseline (0 month (visit 5) to month 4 (visit 9)
2. Change in FVC (percent of predicted normal) from baseline (0 month (visit 5) to month 4 (visit 9)
3. Change in SF-36 from baseline (0 month (visit 5) to month 4 (visit 9)
Funding Ministry for Health & Welfare Affairs, Republic of Korea (HI10C1673 and HI15C0876), and Corestem
Biotechnology, Gyeonggi-do, Republic of Korea

Informed decisions.

Oh 2018 (Continued)
Conflicts of interest SHK received funding for postmarketing survey of Autologous Bone Marrow-Derived Mesenchymal
Stem Cells (HYNR-CS) from Corestem Biotechnology according to the safety guideline of Korean Min-
istry of Food and Drug Safety (KMFDS) after conditional approval of HYNR-CS as an orphan drug from
KMFDS. The remaining authors had nothing to report
Notes In the control group, sham procedures related to stem cell therapy, including BM aspiration, CSF collec-
tion for BM-MSCs suspension and lumbar puncture were not performed due to ethical considerations.
ClinicalTrials.gov ID: NCT01363401
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk All eligible participants were randomised (1:1) into 2 groups using an interac-
tion (selection bias) tive web response system.
Allocation concealment Low risk Interactive web response system was used.
(selection bias)
Blinding of participants High risk Participants were not blinded to study group assignment. There was no sham
and personnel (perfor- procedure (BM aspiration, CSF collection for BM-MSCs suspension or lumbar
mance bias) puncture) performed in the control group, due to ethical considerations.
All outcomes
Blinding of outcome as- Low risk Neurologists and evaluators were blinded to treatment assignments.
sessment (detection bias)
All outcomes
Incomplete outcome data High risk 4 participants in the control group (withdrawal: 2; death: 1; serious adverse
(attrition bias) event: 1) and 1 participant in the MSC group (withdrawal) were excluded from
All outcomes the full analysis set because these events occurred before visit 5 (baseline).
The disproportionate number of dropouts between the control and treatment
groups could affect the balance of confounders between the study groups and,
therefore, we judged this study at high risk for attrition bias.
Selective reporting (re- Low risk All major outcomes appropriate for the phase 2 trial were reported in sufficient
porting bias) detail.
Other bias Low risk We identified no other potential sources of bias.
ALS: amyotrophic lateral sclerosis; ALSFRS-R: Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; AST: aspartate
aminotransferase; ALT: alanine aminotransferase; BM: bone marrow; BM-MSC: bone marrow-derived mesenchymal stem cells; CSF:
cerebrospinal fluid; FVC: forced vital capacity; HBV: hepatitis B virus; HCV: hepatitis C virus; MSC: mesenchymal stem cell; MSC-NTF:
mesenchymal stem cells secreting neurotrophic factors; MND: motor neuron disease; SF-36: 36-item Short Form.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Gabr 2017 Not an RCT. Evaluation of the safety and efficacy of bone marrow-derived MSCs injected intrathe-
cally in restoring damaged motor neurons.
Karussis 2013 Not an RCT. A phase 1/2 clinical trial to evaluate the safety and tolerability of intramuscular and in-
trathecal treatment with autologous MSCs differentiated to secrete neurotrophic factors in people
with ALS/MND.

Informed decisions.

Study Reason for exclusion
Mazzini 2015 Not an RCT. Phase 1 clinical trial using foetal human neural stem cells from natural in utero death
administered into the anterior horns of the spinal cord to test for the safety of both cells and neuro-
surgical procedures in people with ALS/MND.
Nabavi 2019 Not an RCT. To assess the safety and feasibility of intravenous and intrathecal injections of bone
marrow derived mesenchymal stromal cells in people with ALS/MND.
Petrou 2015 Not an RCT. To evaluate the safety and efficacy of transplantation of autologous bone marrow-de-
rived MSCs induced to secrete neurotrophic factors in people with ALS/MND.
ALS/MND: amyotrophic lateral sclerosis/motor neuron disease; MSC: mesenchymal stem cell; RCT: randomised controlled trial.

Characteristics of ongoing studies [ordered by study ID]

NCT01254539
Trial name or title Clinical trial on the use of autologous bone marrow stem cells in amyotrophic lateral sclerosis (Ex-
tension CMN/ELA)
Methods Randomised, double-blind study
Participants Inclusion criteria
1. Diagnosis established using the World Federation of Neurology criteria

2. > 6 and < 36 months of evolution of the disease
3. Bulbar onset
4. Aged > 18 and < 70 years
5. FVC ≥ 50%
6. Total time of oxygen saturation < 90% inferior to 5% of the sleeping time
7. Signed informed consent
Exclusion criteria
1. Neurological or psychiatric disease

2. Need of parenteral or enteral nutrition through percutaneous endoscopic gastrostomy or naso-
gastric tube
3. Concomitant systemic disease
4. Treatment with corticosteroids, immunoglobulins or immunosuppressors in the last 12 months
5. Inclusion in other clinical trials
6. Inability to understand informed consent
Interventions Autologous bone marrow stem cells intraspinal transplantation at T3-T4
Intrathecal infusion of autologous bone marrow stem cells
Intrathecal infusion of placebo (saline solution)
Cell dose not mentioned
1. FVC
Secondary outcomes
1. Neurological variables: ALSFRS, MRC and Norris scales

2. Absence of adverse events
Informed decisions.

NCT01254539 (Continued)
3. Neurophysiological variables: electromyography, polysomnography, evoked potentials
4. Neuroradiological variables: spinal magnetic resonance imaging
5. Respiratory variables: maximal inspiratory pressure, maximal expiratory pressure, sniff nasal,
oxymetry
6. Psychological variables: Health Questionnaire (EuroQol-5D), Profile of Mood States
Starting date October 2010
Contact information Jose María Moraleda Jiménez, MD, PhD; E-mail: paqui iniesta martínez-iniesmar@yahoo.es
Notes Recruitment status completed. Contacted authors. Not yet finished analysis of the results.

NCT02286011
Trial name or title Intramuscular infusion of autologous bone marrow stem cells in people with amyotrophic lateral
sclerosis (TCIM/ELA)
Methods Prospective, randomised, double-blind study
1. Diagnosis of definite or probable ALS/MND according to the criteria established by the World Fed-
eration of Neurology
2. Reasonable assurance of adherence to protocol
3. Neurophysiological data confirming lower motor neuron lesions in the lumbar region
4. Assessment of motor deficits in dorsiflexion of both feet (4 or 5 points on the MRC scale; MRC scale
grade muscle power as 0 = no contraction, 1 = flicker of contraction, 2 = active movement, with
gravity eliminated, 3 = active movement against gravity, 4 = active movement against gravity and
resistance and 5 = normal power)
5. Participant must fulfil all inclusion criteria
Exclusion criteria
1. Diabetes mellitus
2. Other diseases that may present with polyneuropathy
3. Previous history of stroke
4. Prior pathology of the peripheral nervous system affecting 1 or both lower limbs with or without
clinically evident neurological sequelae
5. Pregnant or breastfeeding women
6. Women physiologically capable of becoming pregnant, unless they are using reliable contracep-
tion
7. People with cardiac, renal, hepatic, systemic or immune conditions that could influence survival
during the test
8. Positive serology for hepatitis B, hepatitis C or HIV
9. Clinical and anaesthesiological criteria contraindicating either sedation or extraction of bone
marrow (an altered coagulation system or anticoagulated with inability to withdraw anticoagu-
lation, haemodynamic instability, altered skin puncture site, etc.)
10.Included in other clinical trials in the last 6 months
Interventions Intramuscular infusion of autologous BM-MNC (550 million cells (100–1200 million) diluted in 2 mL
saline) in tibialis anterior muscle of 1 of the lower limbs
Intramuscular infusion of placebo (2 mL saline) in the contralateral lower limb [sic] (control)

Informed decisions.

1. Rate of serious and non-serious adverse events related to cellular therapy in participants with
ALS/MND
Secondary outcomes
1. Estimated number of motor units

2. Compound muscle action potential
3. Fibre density
4. Muscle strength: MRC score
5. Maximum force developed in an isometric contraction of the tibialis anterior muscle
6. Maximum transversal area of the tibialis anterior muscle
Starting date November 2014 (duration: 38 months)
Contact information Natalia García Iniesta +34968381221; E-mail: nagarini@yahoo.es
Notes

NCT02290886
Trial name or title Clinical trial phase I/II, randomised, controlled with placebo, triple blind to evaluate safety, and in-
dications of efficiency of the intravenous administration of the therapy with 3 doses of MSC in par-
ticipants with moderate to severe ALS
Methods Phase 1/2, multicentre, randomised, placebo-controlled, triple-blind study
1. Men and women aged > 18 years

2. Good understanding of the protocol and able to grant informed consent
3. Definite or probable diagnosis of sporadic ALS/MND in agreement with the criteria of El Escorial
criteria, of the World Federation of Neurology
4. FVC ≥ 50% of normal for sex, height and age
5. Disease onset (beginning of symptoms) > 6 months and < 36 months previously
6. Possibility of obtaining ≥ 50 g of adipose tissue
7. Treatment with riluzole for ≥ 1 month before inclusion
Exclusion criteria
1. Any concomitant disease that under investigator's criteria could affect measures of the clinical
variables (hepatic, renal or cardiac insufficiency, diabetes mellitus, etc.)
2. Previous therapy with stem cells
3. Participation in another clinical trial within 3 months prior to entry in this trial
4. Any lymphoproliferative disease
5. Tracheostomy, gastrostomy or both
6. Haemophilia, haemorrhagic diathesis or current anticoagulation therapy
7. Specific hypersensitivities
8. "Medical precedents" of HIV infection or any serious immunocompromised condition
9. Positive HBV or HCV serology
10.Creatinine level (see www.ClinicalTrials.gov)
Interventions Intravenous 1 million autologous MSC
Intravenous 2 million autologous MSC

Informed decisions.

Intravenous 4 million autologous MSC
Intravenous placebo (control)
1. Number of serious unexpected adverse reactions attributable to the treatment

2. Infusion site complications
3. Appearance of a new neurological sign or symptom not attributable to the natural progression
of ALS/MND
Secondary outcomes
1. Change in disease progression

2. Change in muscular force
3. Change in FVC
4. Change in muscular mass estimated by nuclear magnetic resonance imaging of the upper and
low extremities
5. Change in neurophysiological parameters
6. Change in quality of life
7. Need for and time to tracheotomy or permanent assisted ventilation
Starting date July 2014 (duration: 62 months)
Contact information Fernández O; E-mail: oscar.fernandez.sspa@juntadeandalucia.es
Notes

NCT03280056
Trial name or title Safety and efficacy of repeated administrations of NurOwn® in ALS patients
Methods Randomized, double-blind, placebo-controlled multicentre study
1. ALS/MND diagnosed as possible, laboratory-supported probable, probable or definite as defined

by revised El Escorial criteria.
2. Having onset of ALS/MND disease symptoms, including limb weakness within 24 months at the
screening visit.
3. ALSFRS-R ≥ 25 at the screening visit.
4. Upright slow vital capacity measure ≥ 65% of predicted for gender, height and age at the screening
visit
5. Rapid progressors
6. Participants taking a stable dose of riluzole are permitted
7. Citizen or permanent resident of the US or Canadian citizen able to travel to a US site for all fol-
low-up study visits
Exclusion criteria
1. Prior stem cell therapy of any type

2. History of autoimmune or other serious disease (including malignancy and immune deficiency)
that may confound study results
3. Current use of immunosuppressant medication or anticoagulants (per Investigator discretion)
4. Exposure to any other experimental agent or participation in an ALS/MND clinical trial within 30
days prior to screening visit
Informed decisions.

5. Use of RADICAVA (edaravone injection) within 30 days of screening or intent to use edaravone at
any time during the course of the study including the follow-up period
6. Use of non-invasive ventilation (bilevel positive airway pressure), diaphragm pacing system or
invasive ventilation (tracheostomy)
7. Feeding tube
8. Pregnant women or women currently breastfeeding
Interventions Active comparator: NurOwn (MSC-NTF cells): 3 intrathecal administrations of NurOwn (MSC-NTF
cells) at bi-monthly intervals
ALSFRS-R (28 weeks following the first treatment)
Safety (not further specified)
Secondary outcomes
Biomarkers (such as cell-secreted neurotrophic factors, inflammatory factors and cytokines in pg/
mL) in the cerebrospinal fluid as well as in serum samples (time frame: through selected post-treat-
ment time points up to 20 weeks after transplant)
Starting date August 2017
Contact information Ralph Z Kern; E-mail: rkern@brainstom-call.com
Yael D Gothelf; E-mail: ygothelf@brainstom-call.com
Notes
ALS/MND: amyotrophic lateral sclerosis/motor neuron disease; ALSFRS: Amyotrophic Lateral Sclerosis Functional Rating Scale; ALSFRS-R:
Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; ALT: alanine transaminase; AST: aspartate transaminase; BM-MNC: bone
marrow mononuclear cells; FVC: forced vital capacity; HBV: hepatitis B virus; HCV: hepatitis C virus; MRC: Medical Research Council; MSC:
mesenchymal stem cells; MSC-NTF: mesenchymal stem cells secreting neurotrophic factors.

DATA AND ANALYSES

Comparison 1. Autologous bone marrow-mesenchymal stem cells (BM-MSC) versus no treatment
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Functional impairment: change in Amy- 1 56 Mean Difference (IV, Fixed, 95% CI) 3.38 [1.22, 5.54]
otrophic Lateral Sclerosis Functional Rating
Scale – Revised score
2 Respiratory function: change in % forced 1 56 Mean Difference (IV, Fixed, 95% CI) -0.53 [-5.37, 4.31]
vital capacity
3 Quality of life: change in 36-item Short 1 57 Mean Difference (IV, Fixed, 95% CI) 2.77 [-3.50, 9.04]
Form score
4 Survival at 6 months 1 64 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.94, 1.22]

Informed decisions.

Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
5 Adverse events, total 1 64 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.62, 1.19]
6 Serious adverse events 1 64 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.13, 1.72]

Analysis 1.1. Comparison 1 Autologous bone marrow-mesenchymal stem cells (BM-MSC) versus no treatment,
Outcome 1 Functional impairment: change in Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised score.
Study or subgroup BM-MSC No treatment Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Oh 2018 31 -3.1 (3.5) 25 -6.5 (4.5) 100% 3.38[1.22,5.54]

Total *** 31 25 100% 3.38[1.22,5.54]
Heterogeneity: Not applicable
Test for overall effect: Z=3.06(P=0)
Favours no treatment -10 -5 0 5 10 Favours BM-MSC

Analysis 1.2. Comparison 1 Autologous bone marrow-mesenchymal stem cells (BM-MSC)
versus no treatment, Outcome 2 Respiratory function: change in % forced vital capacity.
Oh 2018 31 -11.3 (10.1) 25 -10.7 (8.4) 100% -0.53[-5.37,4.31]

Total *** 31 25 100% -0.53[-5.37,4.31]
Test for overall effect: Z=0.21(P=0.83)

Analysis 1.3. Comparison 1 Autologous bone marrow-mesenchymal stem cells (BM-
MSC) versus no treatment, Outcome 3 Quality of life: change in 36-item Short Form score.
Oh 2018 32 -9.1 (12.8) 25 -11.8 (11.3) 100% 2.77[-3.5,9.04]

Total *** 32 25 100% 2.77[-3.5,9.04]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%


Informed decisions.

Analysis 1.4. Comparison 1 Autologous bone marrow-mesenchymal stem

cells (BM-MSC) versus no treatment, Outcome 4 Survival at 6 months.
Study or subgroup BM-MSC No treatment Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Oh 2018 32/33 28/31 100% 1.07[0.94,1.22]

Total (95% CI) 33 31 100% 1.07[0.94,1.22]
Total events: 32 (BM-MSC), 28 (No treatment)
Favours no treatment 0.5 0.7 1 1.5 2 Favours BM-MSC

cells (BM-MSC) versus no treatment, Outcome 5 Adverse events, total.
Oh 2018 21/33 23/31 100% 0.86[0.62,1.19]

Total (95% CI) 33 31 100% 0.86[0.62,1.19]
Favours BM-MSC 0.2 0.5 1 2 5 Favours no treatment

cells (BM-MSC) versus no treatment, Outcome 6 Serious adverse events.
Oh 2018 3/33 6/31 100% 0.47[0.13,1.72]

Total (95% CI) 33 31 100% 0.47[0.13,1.72]
Favours BM-MSC 0.01 0.1 1 10 100 Favours no treatment

APPENDICES
Appendix 1. Cochrane Neuromuscular Specialised Register via the Cochrane Register of Studies (CRS-Web) search
strategy
Search date 31 July 2019
#1 MeSH DESCRIPTOR Motor Neuron Disease Explode All AND INREGISTER

#2 "motor neuron disease*" or "motor neurone disease*" AND INREGISTER
#3 "motorneuron disease*" or "motorneurone disease*" AND INREGISTER

Informed decisions.

#4 "motoneuron disease*" or "motoneurone disease*" AND INREGISTER

#5 "charcot disease" AND INREGISTER
#6 "amyotrophic lateral sclerosis" AND INREGISTER
#7 als:ti or als:ab or nmd:ti or mnd:ab AND INREGISTER
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7 AND INREGISTER
#9 mononuclear NEAR2 leukocyte* AND INREGISTER
#10 MeSH DESCRIPTOR Stem Cells Explode All AND INREGISTER
#11 "stem cell*" AND INREGISTER
#12 MeSH DESCRIPTOR Stem Cell Transplantation Explode All AND INREGISTER
#13 "bone marrow" AND INREGISTER
#14 mesenchymal NEAR cell* AND INREGISTER
#15 mononuclear NEAR cell* AND INREGISTER
#16 angiogenesis NEAR therap* AND INREGISTER
#17 #9 or #10 or #11 or #12 or #13 or #14 or #15 AND INREGISTER
#18 #8 and #17 AND INREGISTER
Appendix 2. Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS-
Web) search strategy
Search date 31 July 2019
#1 MeSH DESCRIPTOR Motor Neuron Disease Explode All AND CENTRAL:TARGET

#2 "motor neuron disease*" or "motor neurone disease*" AND CENTRAL:TARGET
#3 "motorneuron disease*" or "motorneurone disease*" AND CENTRAL:TARGET
#4 "motoneuron disease*" or "motoneurone disease*" AND CENTRAL:TARGET
#5 "charcot disease" AND CENTRAL:TARGET
#6 "amyotrophic lateral sclerosis" AND CENTRAL:TARGET
#7 als:ti or als:ab or nmd:ti or mnd:ab AND CENTRAL:TARGET
#8 #1 or #2 or #3 or #4 or #5 or #6 or #7 AND CENTRAL:TARGET
#9 mononuclear NEAR2 leukocyte* AND CENTRAL:TARGET
#10 MeSH DESCRIPTOR Stem Cells Explode All AND CENTRAL:TARGET
#11 "stem cell*" AND CENTRAL:TARGET
#12 MeSH DESCRIPTOR Stem Cell Transplantation Explode All AND CENTRAL:TARGET
#13 "bone marrow" AND CENTRAL:TARGET
#14 mesenchymal NEAR cell* AND CENTRAL:TARGET
#15 mononuclear NEAR cell* AND CENTRAL:TARGET
#16 angiogenesis NEAR therap* AND CENTRAL:TARGET
#17 #9 or #10 or #11 or #12 or #13 or #14 or #15 AND CENTRAL:TARGET
#18 #8 and #17 AND CENTRAL:TARGET
Appendix 3. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to July 30, 2019>
Search strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (486353)
2 controlled clinical trial.pt. (93185)
3 randomi#ed.tw. (580003)
4 placebo.ab. (199708)
5 drug therapy.fs. (2127161)
6 randomly.ab. (315646)
7 trial.ab. (472150)
8 groups.ab. (1939321)
9 or/1-8 (4518366)
10 exp animals/ not humans.sh. (4603844)
11 9 not 10 (3913504)
12 exp Motor Neuron Disease/ (26171)
13 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease).mp. (8621)
14 ((Lou Gehrig$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 disease)).mp. (200)
15 charcot disease.tw. (24)
16 Amyotrophic Lateral Sclerosis.mp. (25602)
17 or/12-16 (35296)
18 Leukocytes, Mononuclear/ (35660)

Informed decisions.

19 Mesenchymal Stromal Cells/ (33145)

20 Bone Marrow Transplantation/ (44128)
21 exp stem cells/ (201255)
22 exp Stem Cell Transplantation/ (76955)
23 (mononuclear adj5 cell$1).tw. (81721)
24 mesenchymal stem cell$1.tw. (38264)
25 (angiogenesis adj3 therap$).tw. (3187)
26 bone marrow.tw. (204618)
27 stem cells.tw. (155001)
28 or/18-27 (548288)
29 11 and 17 and 28 (159)
30 remove duplicates from 29 (159)
Appendix 4. Embase (OvidSP) search strategy

Database: Embase <1974 to 2019 July 29>
Search strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (60061)
2 double-blind procedure.sh. (163402)
3 single-blind procedure.sh. (36004)
4 randomized controlled trial.sh. (561727)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (1668280)
6 trial.ti. (276639)
7 controlled clinical trial/ (464227)
8 or/1-7 (1985978)
9 exp animal/ or exp invertebrate/ or animal.hw. or non human/ or nonhuman/ (26239888)
10 human/ or human cell/ or human tissue/ or normal human/ (20033631)
11 9 not 10 (6268194)
12 8 not 11 (1764798)
13 limit 12 to (conference abstracts or embase) (1493112)
14 motor neuron disease/ or amyotrophic lateral sclerosis/ (42033)
15 (moto$1 neuron$1 disease$1 or moto?neuron$1 disease$1).mp. (13637)
16 ((Lou Gehrig$1 adj5 syndrome$1) or (Lou Gehrig$1 adj5 disease)).mp. (227)
17 charcot disease.tw. (28)
18 amyotrophic lateral sclerosis.tw. (28745)
19 or/14-18 (46810)
20 mononuclear cell/ (44111)
21 exp mesenchyme cell/ (78826)
22 exp bone marrow transplantation/ (63495)
23 exp stem cell/ (347407)
24 exp stem cell transplantation/ (141205)
25 (mononuclear adj5 cell$1).tw. (108990)
26 mesenchymal stem cell$1.tw. (56351)
27 (angiogenesis adj3 therap$).tw. (4368)
28 bone marrow.tw. (292794)
29 stem cell$1.tw. (360632)
30 or/20-29 (838941)
31 13 and 19 and 30 (93)
32 remove duplicates from 31 (93)
Appendix 5. ClinicalTrials.gov search strategy

ClinicalTrials.gov basic search
(motor neuron disease OR amyotrophic lateral sclerosis) AND (cell based OR leukocytes OR mesenchymal OR mesenchym OR mononuclear
OR bone marrow OR stem cell OR angiogenesis)
Appendix 6. WHO ICTRP search strategy

WHO ICTRP advanced search
motor neuron disease AND cell-based OR motor neuron disease AND leukocytes OR motor neuron disease AND mesenchymal OR motor
neuron disease AND mesenchym OR motor neuron disease AND mononuclear OR motor neuron disease AND bone marrow OR motor

Informed decisions.

neuron disease AND stem cell OR motor neuron disease AND angiogenesis OR amyotrophic lateral sclerosis AND cell-based OR amyotrophic
lateral sclerosis AND leukocytes OR amyotrophic lateral sclerosis AND mesenchymal OR amyotrophic lateral sclerosis AND mesenchym OR
amyotrophic lateral sclerosis AND mononuclear OR amyotrophic lateral sclerosis AND bone marrow OR amyotrophic lateral sclerosis AND
stem cell OR amyotrophic lateral sclerosis AND angiogenesis.
WHAT'S NEW

Date Event Description
27 November 2018 New citation required and conclusions No studies were eligible for inclusion in the previous review; the
have changed review now includes two randomised controlled trials (RCTs).
15 November 2018 New search has been performed Two RCTs involving 112 participants were eligible for inclusion
in this review. We reported the results of newly included studies,
assessed risk of bias and graded the certainty of the evidence.
We also:
• listed the sources that we handsearched;

• added another scale as an example of functional rating scale
for amyotrophic lateral sclerosis and added the reported min-
imally important difference in Amyotrophic Lateral Sclerosis
Functional Rating Scale.

CONTRIBUTIONS OF AUTHORS
SFAW, ZKL, NML and NAI wrote the review and approved the review in its final form.
SFAW designed the project and review.
SFAW, ZKL and NAI drafted the search strategy.
SFAW, ZKL and NAI performed the study screening and selection.
NML and NAI reviewed the analysis of the search
DECLARATIONS OF INTEREST
SFAW is a consultant haematologist and professor of internal medicine and performed haematopoietic stem cell transplantation for people
with blood and bone marrow diseases. She has been actively involved in many clinical trials utilising cell and cell-based products for blood
cancers and various degenerative conditions. No known conflicts of interest.
ZKL is a neurologist and manages patients with a range of neurological diseases including ALS/MND. No known conflicts of interest.
NAI is a research officer and a clinical study co-ordinator involved in production of clinical grade cell and cell-based products and managing
clinical trials. No known conflict of interest.
NML is a Paediatrician and Neonatologist by training, and a Cochrane Trainer. He has no known conflict of interest.
SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• No sources of support supplied, Malaysia.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
1. In our protocol (Abdul Wahid 2015), we did not specifically state the other sources that we handsearched. In the current review, we
handsearched publications from the following journals: Cytotherapy, Cell Transplantation, Cell Stem Cell and Stem Cells for relevant
Informed decisions.

articles. We searched the Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects (DARE), Health
Technology Assessment (HTA) and National Health Service Economic Evaluation Database (NHSEED) for the original review in 2015 with
no relevant papers found. We did not search them for this update as they are no longer included in the Cochrane Library.
2. We made the following changes to the outcomes for the first version of the review, which had no included studies.
a. The primary outcome originally defined in the protocol was 'Change in Expanded Disability Status Scale (EDSS) or Amyotrophic
Lateral Sclerosis Functional Rating Scale (ALSFRS) at 6 and 12 months.' In this update, we moved the 12-month ALSFRS score to
secondary outcomes and removed the change in EDSS outcome.
b. We specified that the FVC to be reported was upright FVC.
c. We changed the outcome 'Change in compound muscle action potential (CMAP) and neurophysiological index (NI) at 6 and 12
months' to 'Change in compound muscle action potential (CMAP), neurophysiological index (NI), combined motor index (CMI), motor
unit number estimation (MUNE), and motor unit number index (MUNIX) at 6 and 12 months.
d. We added examples of acceptable quality of life scales (such as ALS Assessment Questionnaires, ALSAQ-40 or ALSQ5, Short-Form 36
(SF-36) Health Survey and EQ-5D) at 6 and 12 months (Jenkinson 2000; Jenkinson 2007; Rabin 2001; Ware 1992).
e. We added detail to the specification of our adverse events outcome: "Adverse events include an inflammatory reaction at the cell
injection site, and cardiovascular and thromboembolic complications. We would have reported the rate of adverse events and the
rate of withdrawal from the study." In the present review, we also reported serious adverse events.
3. We removed "Repeat the analysis excluding large studies to assess the effect of these studies on the overall results" from our planned
sensitivity analyses on the advice of the Cochrane Neuromuscular statistician.
4. In the protocol, we specified that the outcomes for inclusion in the 'Summary of findings' table were: EDSS and ALSFRS scales, manual
muscle testing, FVC, survival rate, and adverse events at 12 months. As 12-month data were not available, we reported the longest time
points from the included study, which was four or six months, depending on the outcome.
INDEX TERMS
Medical Subject Headings (MeSH)

*Cell- and Tissue-Based Therapy; Amyotrophic Lateral Sclerosis [complications] [*therapy]; Disease Progression; Quality of Life;
Randomized Controlled Trials as Topic; Vital Capacity
MeSH check words

Humans


Abdul Wahid 2019

Uploaded by

Copyright:

Available Formats

Abdul Wahid 2019

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Abdul Wahid 2019

Uploaded by

Copyright:

Available Formats

Abdul Wahid SF, Law ZK, Ismail NA, Lai NM

Abdul Wahid SF, Law ZK, Ismail NA, Lai NM.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) i

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron

Editorial group: Cochrane Neuromuscular Group.

Data collection and analysis

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 1

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

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 2

Key results and quality of the evidence

The evidence is up to date as of July 2019.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 3

Outcomes Anticipated absolute effects* (95% CI) Relative № of Certain- Comments

Functional impairment, assessed using a Not measured

Muscle strength: manual muscle testing Not measured

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND was found to slow functional deterioration in some people with

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 6

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 10

Figure 1. Study flow diagram.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 11

Interventions and comparators participants (Mazzini 2015), MSC-NTF in 38 participants (Karussis

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 12

Other potential sources of bias Mood state and quality of life

The study did not measure nerve conduction.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 14

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 15

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 17

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 18

Iniesta F, Gomez-Espuch J, Blanquer M, Perez-Espejo MA, Abe 2014

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 19

mechanisms. Cancer Research 2007;67(19):9142-9. [PUBMED: Chen 1996

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 20

Deng 2011 for studying neuroprotection and neurodegeneration.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 21

Kim 2002 Mazzini 2012

Logroscino 2005 Miller 2012

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 22

Prabhakar 2012 Terada 2002

Rabin 1999 Thonhoff 2009

Rabin 2001 Turner 2003

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 23

Characteristics of included studies [ordered by study ID]

Mean age: 51.1 years

Sex: 35 men, 13 women

1. Men and women aged 18–75 years, inclusive

1. Prior stem cell therapy of any type

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 24

Interventions Autologous MSC-NTF cells; cell dose not mentioned

Outcomes Primary outcome

1. Number of participants with adverse events

Funding Funded Brainstorm-Cell Therapeutics

Conflicts of interest Not clearly stated.

Bias Authors' judgement Support for judgement

Methods of sequence generation not stated.

Blinding of participants Unclear risk Quote: "double blind, placebo-controlled."

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease (Review) 25

#4 "motoneuron disease" or "motoneurone disease" AND INREGISTER