





































Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
tanviy@berkeley.edu

Keywords:
Amyotrophic Lateral Sclerosis 
pathogenesis of ALS  
mesenchymal stem cells 
neurodegenerative disease     
SOD1                                      
riluzole                               
astrocytes

Submitted: August 12, 2022 

Accepted: October 24, 2022

Published:  December 28, 2022

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease caused by the 
degeneration of motor neurons in the brain and spinal cord, leading to muscle weakness, 
paralysis, and eventually death. Exactly how and why motor neurons degenerate is still not 
clearly known, but certain pathogenetic mechanisms could explain the process. Current 
treatments and interventions, including pharmacological approaches, are not highly targeted 
and only offer short-lived benefits. No cure for the disease exists to date. However, 
mesenchymal stem cells, which are adult stem cells that are highly accessible and can 
differentiate into different types of tissue, are currently being studied. This review offers 
insight into some of the pathogenetic mechanisms, potential treatments, and how 
mesenchymal stem cell treatment could be the potential cure for ALS. 

Administration of Mesenchymal Stem Cells as   
a Therapeutic for Amyotrophic Lateral Sclerosis
By: Tanvi Yalamanchili, Saahil Mohta and Donna Tran



1. Introduction
ALS is a progressive neurodegenerative disease caused by the loss of brain
connectivity to the muscles. As motor neurons degenerate or die, the
muscles weaken, eventually leading to paralysis1. Motor neurons are
specialized brain cells located in the brain and spinal cord and control the
motor function of the body. There are two types of motor neurons: upper
motor neurons, which originate in the brain, and lower motor neurons,
which send signals from the brain to the spinal cord and then to the target
muscles2. The disease leads to the degeneration of upper motor neurons in
the primary cortex and the degeneration of lower motor neurons in the
brainstem and the spinal cord1.

The word “amyotrophic” comes from Greek roots that mean “without
nourishment to muscles” and refers to the loss of signals nerve cells
normally send to muscle cells. Therefore, an important e�ect of ALS is the
reduction of the blood-brain and blood-spinal cord barriers. These barriers
are responsible for brain homeostasis, regulation of in�ux/e�ux transport,
and protection from damage caused by the debris in the bloodstream7.

ALS was �rst discovered in 1869 by the French neurologist Jean-Martin
Charcot but became more commonly known as Lou Gehrig’s Disease after
the famous baseball player Lou Gehrig was diagnosed with ALS at the age of
36. After being diagnosed, the Yankee player retired soon after as he
experienced symptoms such as loss of strength, and loss of coordination,
making him un�t on the �eld3.

As a progressive disease, ALS causes motor neuron degeneration to worsen
until the patient passes away1. Symptoms in the early stages of the disease
include fatigue, poor balance, slurred speech, and tripping due to
fasciculations (spontaneous muscle contractions/twitches) and atrophy
(loss of muscle tissue)4. As some muscles paralyze, fasciculations continue,
and joints start to become rigid and painful. Walking, eating and breathing
start to become di�cult. Some people have uncontrolled crying or laughter.
In the late stages of the disease, the patients’ voluntary muscles become
paralyzed, and the muscles that help expand and contract the lungs for air
are compromised, leading to respiratory failure5,6.

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Around 5000 people are diagnosed with ALS every year, and someone dies
from the disease every 90 minutes. Once diagnosed, the average life
expectancy is two to �ve years. Although it is most common for the disease
to develop at ages greater than 60 years, it can occur at younger ages as well6.

There are two types of ALS cases: familial ALS (fALS) and sporadic ALS
(sALS)7. Familial ALS occurs due to genetic inheritance, and accounts for
only 5-10% of ALS cases. It has an earlier age of onset compared to sALS6,7.
It is known to primarily take form as a result of gene mutations such as
SOD1 mutations. Over 20 gene mutations have now been identi�ed that
play a role in ALS disease progression. Silence Superoxide Dismutase 1
(SOD1) is a major gene correlated with ALS. Sporadic ALS on the other
hand, although phenotypically indistinguishable from fALS, is not
genetically inherited. As the most common form of ALS, sALS accounts for
90-95% of all cases6,7.

Although the cause for ALS is unknown, the growing evidence points to
the possibility of disease occurrence in humans due to gene-environment
interactions. Exposure to certain toxic substances, viruses, or physical
trauma could cause the disease6. Certain genes, known as “susceptibility
genes,” can trigger a neurodegeneration cascade upon interaction with
certain environmental stimuli and/or factors. Unfortunately, no de�nitive
environmental risk factors have been identi�ed for ALS that can be
replicated8. However, possible associations, based on clinical studies, have
been identi�ed between autoimmune pathology, neuroin�ammation, head
injury/trauma, metabolic disease, and ALS—speci�cally, the pathogenesis of
ALS8.

There are four main pathogenetic mechanisms that may explain the
degeneration of motor neurons; these include mitochondrial dysfunction,
glutamate excitotoxicity, oxidative stress, and in�ammation. Current
treatments include FDA-approved drugs such as riluzole and edaravone9. In
addition, many treatments are being tested to reduce the e�ect of these
mechanisms, including but not limited to, SOD1 gene therapy, and
astrocyte transplantation9. However, the treatments mentioned above are

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either short-lived or only target one of the pathogenetic mechanisms. Of the
treatments being studied, Mesenchymal Stem Cells (MSCs) stand out as a
potential cure for ALS. MSCs not only target the pathogenetic mechanisms
to replace dead cells with healthy, di�erentiated cells but they also repair
damaged cells10.

Stem cells are unique in their ability to migrate to damaged tissues and/or
sites, stimulate tissue repair and regeneration, and di�erentiate in response
to extracellular signals. MSCs are adult stem cells that contain properties of
self-renewal, immunosuppressive potential, and potency for
trans-di�erentiation into motor neurons10. In particular, MSCs have been
shown to be a promising therapeutic for ALS in preclinical and clinical
trials. MSCs have the ability to stimulate tissue repair by di�erentiating into
motor neuron cells, repair damaged neurons, and rebuild the
brain-to-muscle connectivity10. This review o�ers insight into the di�erent
pathogenetic mechanisms of ALS, current treatment options, and why
MSCs might o�er a cure.

2. The Pathogenetic Mechanisms of ALS
2.1. Mitochondrial Dysfunction

There are a few pathogenetic mechanisms that may explain the disease
progression. Of those, mitochondrial damage is an important pathogenetic
mechanism to consider. Mitochondria is the major organelle responsible for
many cellular processes such as producing energy, conducting cellular
respiration, and maintaining calcium homeostasis8. This organelle is also
known to play a key role in the process of apoptosis—a type of cell death
activated by a series of molecular steps known as the caspase cascade. This
pathway is often used by the body to remove unneeded or abnormal cells11.
Because the mitochondria play a key role in regulating apoptosis, damage to
this organelle within motor neurons can alter its ability to regulate the
process. In ALS patients, the mitochondria that are present in their spinal
motor neurons, skeletal muscles, and intramuscular nerves are swollen and
vacuolated. Speci�cally, these swollen mitochondria activate the apoptotic
caspase cascade, causing the death of the motor neurons12.

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Additionally, deposits of the misfolded SOD1 enzymes and altered protein
expression in the mitochondria further alter the physiological function of
the organelle9. A de�cit in ATP production a�ects the cell’s energy
homeostasis and causes a defective energy metabolism. Alterations in the
energy metabolism weaken the cell’s health. Mitochondria with an altered
structure or biochemical imbalance are prone to triggering apoptosis, thus
leading to neuronal degeneration.

Mitochondria are responsible for regulating calcium levels as well. In ALS
models, scientists have reported dysregulation of intracellular Ca2+ in motor
neurons. Chronic elevations of cytosolic Ca2+ due to neuronal
hyperexcitability elicit an increase in mitochondrial Ca2+ uptake and a
decrease in mitochondrial Ca2+ e�ux. When this condition is combined
with altered mitochondrial calcium regulation, excitatory mitochondrial
toxicity occurs, leading to dendritic mitophagy, mitochondrial depletion,
and eventually dendritic atrophy and neurodegeneration13. Overall, Ca2+

dysregulation in motor neurons is at the cornerstone of disease progression
of ALS13.

2.2. Glutamate Excitotoxicity
Glutamate excitotoxicity is another pathogenetic mechanism that can
provide an explanation as to how motor neurons degenerate in ALS
patients. Glutamate is a principal excitatory neurotransmitter in the central
nervous system (CNS) and plays a key role in triggering action potentials14.
Neurotransmitters are chemical messengers that send signals from one nerve
cell to a target cell, which could be a nerve cell, a motor cell, or a gland15.
Glutamate sends signals within the CNS, which is made up of the brain and
spinal cord. This neurotransmitter is originally generated in the presynaptic
cleft terminal, exits through exocytosis, then moves across the synaptic cleft
in order to activate postsynaptic receptors in the dendrites of postsynaptic
motor neurons, which triggers action potentials16,17. The synaptic cleft is the
space neurotransmitters travel through to send messages from one neuron
to the next.

Glutamate reuptake transporters remove glutamate from the synaptic cleft
to regulate the concentration of the neurotransmitter in the synaptic cleft,

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getting rid of excitatory stimuli along with it16. High glutamate
concentration in the synaptic cleft leads to excitotoxicity, which can either
result from increased synaptic levels of glutamate or greater glutamate
sensitivity in the postsynaptic terminal9. Overall, excitotoxicity occurs due
to prolonged activation of glutamate receptors, which eventually leads to
the degeneration and death of the motor neurons involved, induced
through excessive neuronal �ring18. ALS patients reported having lower
levels of glutamate transporters, which leads to an increased concentration
of this neurotransmitter in the synaptic cleft and an overactivation of
glutamate receptors, determining the level of excitotoxicity within the
neurons7.

As a key regulator of neuronal activity due to the role it plays in apoptosis
and neurotransmitter release, calcium plays an important role in
excitotoxicity19. The activation of glutamate receptors opens calcium
channels, allowing calcium to enter the cell. The calcium-bu�ering proteins
in motor neurons make motor neurons sensitive to excitotoxicity. If
intracellular calcium levels get too high, mitochondrial damage may result
and lead to the activation of biochemical processes that a�ect neuronal
degeneration13. Additionally, motor neurons are especially sensitive to
excitotoxicity due to the high calcium permeability of these cells13. With
more calcium able to enter the cells, intracellular calcium levels get high and
lead to cell damage that induces the degeneration of motor neurons.
Therefore, increasing the concentration of glutamate transporters would
decrease the synaptic glutamate concentration and reduce excitotoxicity
levels to help prevent degeneration13.

2.3. Neuroin�ammation and Glial Cells
Neuroin�ammation is an immune response in the CNS to neuronal
damage and plays an important role in the pathogenesis of ALS. An
immune response is the body’s way of �ghting foreign substances to heal
damage, but this can become harmful when accompanying a disease20.
Neuroin�ammation is characterized by overactivated microglia, reactive
astrocytes, and in�ltrating immune cells such as lymphocytes into the site of
neuronal injury9. As the �rst line of defense within the CNS, microglia are
activated and respond to signals released by damaged cells, more speci�cally

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injured motor neurons21. Glial cells refer to the cells present in large
quantities in the CNS and function as mediators of neuronal activity by
surrounding and separating neurons; they can also play a part in
regenerating damaged neurons22. Astrocytes are a type of glial cells that are
closely associated with motor neurons. However, when the damage becomes
worse, astrocytes and motor neurons release mutated SOD1 proteins, which
activate pro-in�ammatory microglia.

There are two kinds of microglia: M1 type microglia and M2 type microglia.
M1 microglia are proin�ammatory and secrete ROS and other neurotoxic
molecules, which contribute to neuronal death9. By contrast, M2 microglia
are anti-in�ammatory and secrete neurotrophic factors—molecules that
enable neurons to maintain connections with other neurons23. During the
early stage of the disease, microglia with an M2 phenotype are present24. As
the disease progresses, however, astrocytes and motor neurons activate
microglia that present with an M1 phenotype9. These M1 microglia release
ROS and other neurotoxic molecules that contribute to neuronal
degeneration.

Additionally, astrocytes that are supposed to support neurons by using
glutamate receptors to maintain low synaptic glutamate levels present
di�erently in ALS patients who have astrocytes with the mutant SOD1
gene, which instead induces motor neuron degeneration. They
downregulate the glutamate transporters, which in turn limit the amount of
glutamate to be uptaken by the receptors out of the synaptic cleft9. They
also secrete in�ammatory molecules, and this in�ammatory response further
contributes to the alteration and degeneration of motor neurons16. While
neuroin�ammation is not the initial cause as to why motor neurons
degenerate, it is a response to the damaged neurons that further exacerbates
degeneration20. Reducing the in�ammatory e�ects caused by overactivated
microglia and reactive astrocytes could potentially be used to reduce
neuroin�ammation and slow neuronal degeneration.

2.4. SOD1 and Oxidative Stress
Oxidative stress is a cellular state motor neurons undergo that progresses
and contributes to ALS pathogenesis. ALS patients have been shown to

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have an increased level of oxidation, meaning they are in oxidative stress.
Oxidative stress occurs when reactive oxygen species (ROS) accumulate
within the cell or are being produced at a greater rate than they are removed,
meaning the cell is unable to repair the stress25. This causes permanent
damage to cell structures and macromolecules. The term ROS embodies
superoxide, ozone, and all other reactive species that contain oxygen26.
SOD1 is a major enzyme used to prevent oxidative damage28.

Most neurodegenerative diseases are characterized by the cellular
accumulation of misfolded proteins. In ALS mutant SOD1 proteins
aggregate and alter normal cell function. The original function of the SOD1
enzymes is to reduce the reactive oxygen species (ROS) released from the
mitochondria. They do this by catalyzing the conversion from superoxide
into oxygen and hydrogen peroxide. This process plays an important role in
the antioxidant defense of motor neurons16. However, in ALS, the mutant
SOD1 enzymes no longer function as important molecules for antioxidant
activity, but instead create oxidative stress. They convert antioxidants into
superoxide by donating electrons from antioxidants to molecular oxygen. In
this case, oxidative stress is not caused by a decrease or loss in the function of
SOD1 but rather a new toxic function of the enzyme9.

Not only is oxidative stress linked to the progression of ALS, it also
contributes to the other pathogenetic mechanisms as well. When mutant
SOD1 enzymes are present in the mitochondria, the mitochondria produces
an abnormal amount of ROS, which, in turn, exacerbates oxidative stress16.
Furthermore, this also determines excitatory damage and therefore motor
neuron degeneration.

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Figure 1. The four pathogenetic mechanisms of ALS: Mitochondrial Dysfunction, Glutamate
Excitotoxicity, Inflammation, Oxidative Stress.

3. Novel Cell Therapies
3.1. Pharmacological Approaches
Pharmacological therapies for ALS target neurodegeneration by stagnating
or impeding the death of motor neurons. Riluzole is the �rst FDA approved
drug for ALS after it initially proved to be successful in clinical trials in the
1990s28. Common brand names of riluzole are Exservan, Rilutek, and
Tiglutik. Since its successful administration, new drugs including edaravone
and AMX0035 have been studied to evaluate their e�cacy against
predecessors.

Riluzole functions by protecting motor neuron cell lines from glutamate
stress. Glutamate is an essential neural excitatory neurotransmitter which
facilitates proper signal propagation throughout the central nervous
system29. Imbalances in glutamate levels can a�ect nerve health and
contribute to cell death. Like many neurodegenerative therapeutics, riluzole
prevents excitotoxicity and slows degeneration of motor neurons. The most
prominent clinical trials involving solely riluzole as a therapeutic for ALS are
from the late 20th century where the drug was initially found to be a
successful treatment. In a 1994 clinical trial, conducted before the FDA
approval of riluzole in 1995, riluzole slowed ALS progression by inhibiting

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disease processes in the CNS30. Factors including death rate and
deterioration of muscle strength were higher for the placebo group than
those treated with riluzole in a one year period. The study also noted that a
subsequent experiment on dosage should be conducted to which
researchers in 1996 tested the impact of riluzole dose-ranges on ALS
patients to determine that the prescription amount with the best
bene�t-to-risk ratio is a 100 mg dose, further con�rming the success of
riluzole.

While a complete understanding of riluzole’s mechanism of action has not
been established, properties including its ability to inhibit glutamate release
and inactivate voltage-gated sodium channels associated with damaged
neurons are attributed to its e�ectiveness for ALS31. Neuroprotective drugs
like riluzole function by binding to voltage-gated sodium (Nav) channels to
keep them in an open and inactivated conformation32. It also inhibits Na+

currents which regulate excitability imbalances to prevent neuronal damage.
A common brand of riluzole is RILUTEK® which o�ers the medication in
the form of a prescription pill. In 1995, it became the �rst drug to receive
FDA approval for a treatment of ALS as it proved to “extend survival and/or
time to tracheostomy” in clinical trials33. In the original clinical trials, it was
estimated that the patients treated with riluzole have longer survival times of
two to three months. However, a retrospective statistical analysis on
population studies of ALS compared the mean survival rate between treated
and non-treated patients to suggest that riluzole may even extend survival by
six to 19 months, longer than the original expectancy34.

Although riluzole is a favorable option, advances in pharmacology have been
geared towards new drugs and additive treatments to improve e�cacy. In
May of 2017, the FDA approved the second targeted drug intended to slow
ALS progression: edaravone. The most common formulation is
RADICAVA IV which has shown signs of selective e�ectuality35. Unlike
riluzole which targets excitotoxicity, edaravone is an antioxidant– a
compound inhibiting lipid oxidation to prevent the production of free
radicals and chain reactions that may induce cell damage36. By reacting with
radical species, this antioxidant captures unstable reactive oxygen species
because a large concentration of these molecules contributes to the

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degeneration of motor neurons. An active phase 3 clinical trial is currently
evaluating the safety and e�cacy of oral edaravone for ALS patients based
on the ALS Functional Rating Scale- Revised (ALSFRS-R) score which
observes lifestyle changes such as independence, speech, and mobility37. The
�rst version of this drug was administered via intravenous infusion, a
drug-delivery method administered directly into a vein using a cannula,
which received FDA approval on May 5, 2017. The doses are given in slow
and set treatment cycles to observe for signs of hypersensitivity. The
infusion can take up to an hour and must be performed by a healthcare
provider. On May 12, 2022, Radicava Oral Suspension was FDA approved,
which grants the user more �exibility in administering treatment.

Prior to Radicava’s oral formulation, di�erences between the two
treatments such as absorption and distribution were more observable38.
While riluzole is in a more convenient tablet form, injections of edaravone
do not face issues with absorption, and there may be more transport across
the brain blood barrier (BBB), a semipermeable membrane facilitating the
transport of molecules and substances from the bloodstream to the brain.
Cohort studies have also observed the e�ects of using intravenous edaravone
in conjunction with riluzole, but there was no improvement in ALS in
comparison to standard riluzole therapy39. Since the issue of convenience is
no longer a dividing factor, new research is geared towards testing the
variation between both oral forms in e�cacy for ALS treatment.

Another novel drug that is currently being tested in clinical trials is
AMX0035, used as an oral combination therapy of sodium phenylbutyrate
(SPB) and taurursodiol (TURSO) to block cell death mechanisms37.
AMX0035 was developed by Amylyx Pharmaceuticals, Inc., and on
September 29, 2022, the FDA approved this drug as the newest therapeutic
for ALS41. It will be sold to patients in the U.S. under the name Relyvrio,
and it proved successful in clinical trials, with patients reporting less ALS
symptoms under the treatment in comparison to a placebo40. In the
brie�ngs between the company and the FDA, it was also noted in the results
of their clinical trials that patients who were randomly assigned to receive
AMX0035 also showed statistically signi�cant increases in survival duration
of around �ve months longer than the placebo. This value is comparable to

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the survival bene�ts of riluzole and edaravone which are three and six
months, respectively. After nearly a decade of developing a new
combination drug for ALS, Amylyx’s co-founders Justin Klee and Josh
Cohen became successful at providing the ALS community with newfound
hope for an improved lifestyle.

This drug targets two of the various mechanisms contributing to disease
propagation: ER stress and mitochondrial stress. SPB alleviates toxicity
from ER stress, increasing the number of heat-shock proteins (HSPs) which
provide neuroprotection42. Likewise, TURSO reduces mitochondrial stress
by increasing the mitochondrial selectivity and cell's threshold for apoptosis.
In a clinical trial conducted by the Northeast Amyotrophic Lateral Sclerosis
Consortium (NEALS) and Amylyx Pharmaceuticals, patients received a 2:1
ratio of SPB to TURSO dissolved and taken orally or through a feeding
tube. After the six month period of daily medication, there was a reduction
in the rate of dysfunction based on the ALSFRS-R. ALS patients involved
in this trial were still taking riluzole, edaravone, or both, but researchers did
not observe notable di�erences in e�cacy. In the near future, more
information on AMX0035 for ALS treatment may be obtained if it receives
FDA approval and becomes accessible to ALS patients as a viable option
alongside riluzole and edaravone.

Each ALS therapy has its own bene�ts and caveats, and due to the diversity
in ALS types and ALS patients, one form may prove to be more e�ective in
reducing neurodegeneration than other. As the �rst drug for ALS, riluzole
remains more e�ective with extensive results from clinical trials to prove its
e�cacy. Advancements in the development of newer drugs such as
edaravone and AMX0035 provide increased con�dence in the possibility of
slowing the rate of ALS progression. Similarly, stakeholders are increasingly
interested in new therapies for increased access and improvements on the
ALS rating scale. While none of the drugs approved for ALS are a complete
cure because they solely function to delay disease propagation, new
approaches are still being tested for factors including an increase in survival
probability, safety, and long-term consequences, riluzole still remains the
most prevalent treatment.

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Table 1. A comparison table of the drugs riluzole, edaravone, and AMX0035 for ALS

4. Gene Therapy
Since pharmacological therapeutics have yet to eradicate and cure ALS, gene
therapy approaches have also been explored as a potential solution. Gene
therapy can be divided into two types: (1) non-viral gene therapy where
nucleic acid sequences are delivered to the host cell for pathological
modi�cation; and (2) viral gene therapy in which genetically-modi�ed
viruses are used as viral vectors to deliver sequences. Antisense
oligonucleotide (ASO) drugs belong to category one and are used in
pre-clinical trials of SOD1-fALS. Superoxide dismutase 1 (SOD1) is the �rst
of 30 ALS-related genes currently discovered. Oxidative damage is a result of
an abundance of ROS such as superoxide in the cell, making it unable to
prevent cellular stress. SOD1 prevents oxidative damage and reduces
superoxide leakage from mitochondria by catalyzing the conversion of
superoxide into oxygen and hydrogen peroxide. Mutations in the SOD1
gene contribute to the pathogenesis of familial ALS and accounts for
15–20% of fALS cases, and begin with the misfolding of the gene which
causes it to be degraded by the ubiquitin/proteasome system (UPS)18.
However, once a large concentration of misfolded proteins accumulate, this
disrupts proteostasis–the regulation of proteins from synthesis to
degradation–and retriggers autophagocytosis to increase the number of
autophagosomes for the removal of dysfunctional cellular constituents16.
Over time, an accumulation of mutated SOD1 proteins induces cell stress
responses, resulting in disease pathogenesis. A buildup of misfolded mutant
SOD1 proteins in the mitochondria can adversely a�ect physiological
function of the organelle. Speci�cally, studies have noted irregularities in the

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production of ATP and ROS which signal cell survival and cell death,
energy and calcium homeostasis, and apoptosis in mitochondrial transport
along axons9.

An ASO used to target SOD1 mRNA is Tofersen (BIIB067), previously
‘IONIS-SOD1Rx.’ It relies on Ribonuclease H (RNase H), an
endoribonuclease enzyme that cleaves the RNA from the RNA/DNA
hybrid, to degrade SOD1 mRNA and prevent the production of toxic
SOD1 proteins18. In a phase 1/2 clinical trial, ALS patients with a SOD1
mutation received multiple doses of Tofersen, and results showed that
patients treated with the greatest concentration of the ASO had lower
SOD1 protein levels by 36%. Also, a decline in the reduction in the
ALSFRS-R score was observed. However, since the drug was delivered via
an intrathecal lumbar puncture, adverse e�ects including headache and back
pain were common consequences. In another approach, researchers relied
on a lentivirus encoding for an RNA silencing (siRNA) gene that catalyzes
the selective degradation of SOD1-mRNA. The injection of this virus in the
muscle or directly in the spinal cord of transgenic mouse models of ALS
showed reduced SOD1 expression delaying the neurodegeneration, but data
about the slowing down of the disease progression and survival is
controversial and requires further study9.

Gene therapy targeting the many ALS-related genes can prevent disease
proliferation by directly preventing mutations at the source. SOD1
mutations can lead to excitotoxicity, mitochondrial dysfunction, and ER
stress which increases the likeliness of motor neuron degeneration. The
appeal of this form of treatment is that the di�erent genes can be
individually suppressed by ASO’s like Tofersen to reduce the degree of toxic
variants. To optimize gene therapy for ALS, the pathological mechanisms
and roles that the genes play must be well understood and develop a barrier
for further propagation of neurotoxic factors. The limitations and
challenges associated with this approach are that it is mostly used to treat
fALS cases and very few sALS cases.

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Figure 2. Pathways linking SOD1 mutations to ALS pathology

5. Astrocyte Transplantation
The most abundant glial cells within the CNS are astrocytes, a form of brain
cell that regulates neural functions through signal di�usion.
Correspondingly, they are necessary in the CNS for neuronal survival. Any
changes including stress or injury to the CNS cause astrocytes to transition
from healthy astrocytes to A1-type neurotoxic astrocytes which promote
degeneration of motor neurons43. The progression in toxicity of healthy
motor neurons causes a loss in homeostatic functions or gain of toxic
functions. Astrocytes of ALS patients are characterized as A1-type, and
targeted therapies to control the proliferation of neurotoxic astrocytes are
currently being tested for ALS.

Astrocyte-targeted therapy involves restoring the function of neurotoxic
astrocytes through the transplantation of healthy astrocytes43. While this
decreases the concentration of misfolded proteins and aids in
neuroprotection, there is also the risk that these healthy astrocytes can
undergo the transition to A1-type astrocytes when they are introduced to
the CNS of ALS patients. This new environment can be toxic to the new
cells due to the large accumulation of misfolded proteins. Although it has

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been deduced that astrocytes secrete neuroprotective factors that di�use to
the motor neurons, later mechanisms including their attachment and
long-term survival need to be further explored.

In a phase 1/2A trial, researchers from Cedars-Sinai Medical Center are
hoping to �nd a long-lasting solution to ALS by testing the e�ectiveness of
their engineered neural progenitor cells which di�erentiate into astrocytes
inside the body to secrete the GDNF protein, promoting astrocyte
survival44. CNS10-NPC-GDNF are progenitor cells which will release
paracrine factors inside the body. As they release GDNF, this
neuroprotective factor is also transferred to dying motor neurons in the
motor cortex. Two doses of adult stem cells will be delivered to the cortical
area of the human primary motor cortex (M1) as researchers observe for
signs of repaired upper motor neurons and improvement in hand function.
Signs of potential e�cacy will be determined by comparing the di�erence in
rate of loss of hand strength between the two sides. Studies relating
ALS-genes to astrocyte therapies noted that mSOD1-expressing astrocytes
induced selective death of spinal motor neurons, so a potential solution
could be the transplantation of healthy astrocytes or selective silencing of
the mSOD1 gene in astrocytes.

While many hypotheses are developed, it is believed that transplanting
healthy astrocytes will generate a better environment for the motor neurons.
Therefore, the molecular pathology of astrocytes in ALS patients needs to
be further studied. Once the healthy cells are delivered, the pathway it takes
for di�usion and speci�c function remains unknown45. While this
treatment is appealing because it has the potential of restricting the
propagation of toxic cells and slowing degeneration, transplanted cells can
still transform into A1 reactive astrocytes once they are introduced to a
more neurotoxic environment. Under excitotoxic conditions, ALS neurons
and astrocytes can be more sensitive to neuromodulation, so it is pivotal to
developing novel cell therapies for ALS.

6. Stem Cells
Because the focus of this paper is the application of mesenchymal stem cells

(MSC) as a therapeutic for ALS, it is imperative to broadly consider stem

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cells, their capabilities, and their advances in pertinence to regenerative
medicine (a process by which healthy cells are introduced in order to replace
cells that have been adversely impacted by disease) and disease
therapeutics46. Stem cells are cells from which di�erentiated daughter cells,
or cells with a specialized function, can be engendered within the human
body. Daughter cells are cells that result from the mitotic or meiotic
reproductive division of a singular cell, and possess a speci�c function;
examples include epithelial cells, adipose stromal cells, and smooth muscle
cells. Furthermore, these cells are undi�erentiated and are typically sourced
from adult, fetal, and embryonic tissue, in addition to di�erentiated somatic
cells47.

There are four main forms of stem cells: Adult, Embryonic, Induced
Pluripotent, and Mesenchymal48.

6.1. Adult Stem Cells
Adult stem cells are commonly regarded as tissue-speci�c or somatic stem
cells, and are found in a wide range of tissues, including the brain, heart,
liver, and bone marrow. They can facilitate the creation of various cell types
upon injury, but the degree to which this di�erentiation can occur is limited
in comparison to embryonic stem cells. Adult stem cells are multipotent, or
limited to di�erentiating into the specialized cell type in the tissue or organ
of residence. They can also be utilized for general maintenance of tissue and
organs and have the capacity to maintain and repair organs and bodily
tissue, which can give rise to cell regeneration, thus indicative of the role
stem cells can play within regenerative medicine49, 50.

6.2. Embryonic Stem Cells
Embryonic stem cells (ESCs) are conventionally sourced from embryos
three to �ve years of age and are more versatile in comparison to adult stem
cells because they are pluripotent, or capable of giving rise to a variety of cell
types not limited to their organ or tissue of residence. As a result, they are
more versatile and have the capability of tissue/organ regeneration and
repair51. However, embryonic stem cells have a higher probability of being
rejected by the host, and their use is ethically controversial by virtue of the

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fact that the destruction of human embryos is necessary in order to obtain
ESCs52.

6.3. Induced Pluripotent Stem Cells
Induced pluripotent stem cells are a class of pluripotent cells that are
commonly derived from blood or skin cells and have been genetically
engineered into an embryonic-like state in order to behave as ESCs53.
Mesenchymal stem cells, the subject of this paper, are a subgroup of adult
multipotent stromal cells that are derived from adipose tissue, umbilical
cord tissue, amniotic �uid, and bone marrow, and have the capacity to
di�erentiate into numerous cell lines54. Stromal cells comprise the
connective tissues that surround bodily tissues and organs and are separate
from the stroma.

Table 2. A comparison of adult, embryonic, induced pluripotent, and mesenchymal stem cells

Stem cells are especially signi�cant and have been the subject of intensive
study due to the fact that they are the only cell that can naturally develop
and di�erentiate into varying cell types primarily through the autocrine
production of immunomodulatory molecules, bioactive molecules stored
within extracellular vesicles, and growth factors such as the vascular
endothelial growth factor (VEGF)47. As a result, stem cells could,
theoretically, limitlessly participate in cell division in order to replace cells
within damaged tissue55. They have the unique ability to di�erentiate in
response to the microenvironment in which they have been directed

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toward56. It is also important to consider, though, that stem cells need to be
carefully selected according to their biological capacity to survive within the
host organism (where the cells are transplanted), and their ability to
di�erentiate and migrate to various tissues. The upsides and downsides of
each form of stem cells must be evaluated upon consideration for disease
treatment or regeneration. On an interdisciplinary scale, however, because
the treatment options for neurological diseases remain heavily limited and
drug approval rates remain poor in comparison to other therapeutic areas,
the implementation of stem cells carries immense potential for patients
a�icted with disorders such as ALS. Furthermore, numerous degenerative
diseases involve an improper functioning or loss of specialized cells within
the body and there is an imbalance between the supply and demand of
potential donors and their cells within their organs or tissues. Speci�cally,
the supply of donors is currently unable to ful�ll the demand of
replacement cells. As such, stem cells could serve as a solution, continuously
producing viable cells that could replace damaged or injured tissues and thus
address a number of a�ictions55.

To date, stem cells have been implemented for the treatment of diseases such
as amyloidosis, germ cell tumors, and certain cancers through autologous
(obtained from the same individual) and allogenic (obtained from a source
outside the individual, such as a donor) transplantation. With cancers,
speci�cally, stem cells have been implemented to replace cells that have been
adversely impacted by the cancer pathogenesis itself or chemotherapy. While
stem cells are continually being utilized for the treatment and maintenance
of a myriad of diseases, further research is necessary to fully elucidate the
pathogenetic mechanisms by which stem cells function, to properly isolate
and identify stem cells to avoid immunological rejection to the greatest
extent possible, and to address the predisposition of induced pluripotent
stem cells to tumorigenesis, or the formation of tumors in vivo57, 55.

6.4. Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) are a class of stem cells - multipotent and
non-hematopoietic stromal cells - which are conventionally derived from
adult and fetal tissue, such as skeletal muscle, the placenta, blood, adipose,
and the umbilical cord7. MSCs have been demonstrated to take residence

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within most connective tissues in the human body. This high availability
within human tissues makes MSCs accessible as a disease therapeutic. Since
MSCs are multipotent, they have a high di�erentiation plasticity, or a
capability of trans-di�erentiating into multiple specialized cell types58.

Transdi�erentiation is the process by which a cell can be made to
di�erentiate from one cell type into another through genetic
reprogramming. For instance, they are able to di�erentiate into nerve, heart
muscle, liver, and endothelial cells, in addition to the germ layers - the
ectoderm, mesoderm, and endoderm. Furthermore, MSCs are capable of
di�erentiating into neural, glial, and astrocyte-like cells, which can be
signi�cant in pertinence to their utilization as a treatment for ALS and
similar neurodegenerative diseases as this indicates their ability to e�ectively
function as motor or dopaminergic neurons. This in-vitro di�erentiation
potential of MSCs to generate a myriad of cell types that could replace lost
cells within injured tissue has been a signi�cant justi�cation for the use of
MSCs themselves59.

MSCs possess several advantages which increase their potential of being
implemented in disease therapeutics, such as an ability of self-renewal (the
process by which stem cells continually divide to produce additional
undi�erentiated stem cells), their ease of isolation, and a decreased
susceptibility to tumorigenesis (formation and accumulation of malignancy
and malignant properties within cells). In addition, there is no speci�c
immunosuppressive treatment that is necessary or otherwise warranted
upon the transplantation of MSCs, as demonstrated by the fact that studies
have indicated that MSCs are immunosuppressive both in vivo and in
vitro9,60. Typically, MSCs employ this immunosuppressive e�ect on T cells,
which are a major component of the adaptive immune system. Most
signi�cantly, however, the therapeutic e�ects of MSCs are largely associated
with their immunomodulatory e�ects, which include MSCs’ regulation of
lymphocytes that are associated with the innate and adaptive immune
system8.

Immunomodulation is the modulation or alteration of the immune system,
as determined by the activation or suppression of immunomodulating

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agents such as cytokines, vaccines, and monoclonal antibodies. Speci�cally,
MSCs are able to regulate T cell proliferation and have the potency to
upregulate regulatory T cell function, thus simultaneously highlighting
their immunosuppressive abilities because the regulatory T cells function to
suppress the body’s immune response, allowing for a maintenance of
homeostasis. For this reason, there have been proposals for the application
of MSCs to the treatment of autoimmune diseases, which are a category of
diseases in which healthy cells are attacked by the body’s immune system.
MSCs also regulate their immunomodulatory function in accordance with
micro environmental and in�ammatory conditions, indicative of the high
level of therapeutic plasticity of MSCs (they have a potential of being
applied in order to treat a myriad of medical conditions).

MSCs function upon transplantation through various methods. One such
method is cell fusion, which is the process of a cell interacting with nearby
cells in order to form a multicellular assemblage with a universal function.
For instance, the fusion of MSCs with rodent Purkinje cells was observed,
and these fused cells were implemented to improve the therapy of
neurodegenerative disorders and disorders involving the cerebellum56.
Furthermore, mitochondrial transfer is a unique mechanism of action of
MSCs, and is the process in which cells transfer mitochondria to
neighboring injured cells (thus replacing damaged mitochondria and aiding
in the restoration of cellular function). Additionally, the secretion of
extracellular vesicles (exosomes) by MSCs is a similarly important
mechanism of action. MSC exosomes are secreted into the extracellular
space with multivesicular bodies within MSCs fused with the cellular
membrane59. Extracellular vesicles have the potency to transport essential
macromolecules such as genetic material to neighboring cells through
endocytosis to maintain physiological homeostasis, and as such, carry a
potential therapeutic application. Studies have demonstrated that the
exosomes secreted by MSCs possess anti-in�ammatory and regenerative
properties in pertinence to traumatic brain injury, stroke, perinatal brain
injury, and wound healing61, highlighting that MSC-derived exosomes are
crucial to the proper function and therapeutic properties of MSCs as a
whole.

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There are certain characteristics of MSCs that aid in their applications
within regenerative medicine56. MSCs have the ability to form colonies,
which can be measured by the term “colony forming unit” (CFU). A CFU is
a measure of the number of viable cells within a sample that are able to
multiply through binary �ssion. This is one of the primary functional
characteristics of MSCs, which highlights their ability to proliferate upon
transplantation and which would reasonably eliminate (1) the need for
consecutive transplantations and (2) possible supply shortages associated
with the availability of MSCs. In addition, while it has been discussed above
that MSCs have a high di�erentiation plasticity as compared to other stem
cells, MSCs have the unique capability of undergoing trilineage
di�erentiation into adipocytes (fat cells which store energy as fat),
chondrocytes (key component of cartilage tissue), and osteocytes (bone cells
which make up approximately 90-95% of cells within bone tissue).
Furthermore, the telomerase activity of MSCs is signi�cant as their activity
is typically augmented within MSCs. Telomeres are the end caps of
chromosomes which shorten with cell replication and division, and
similarly, telomerase is the enzyme responsible for the region of the
telomeric region at the 3’ ends of chromosomes. Telomeres also protect
chromosomal ends from degradation and improper DNA recombination
(which can result in apoptosis). As such, an increased telomerase activity is
directly correlated with a longer cell lifespan. Since the telomerase activity is
augmented within MSCs, MSCs have a longer period of survival. The
telomerase activity and the telomere lengths can also be analyzed as a quality
control measure to aid in the selection of MSCS for therapeutic
applications.

Studies have demonstrated that MSCs have the capability and potential of
being trans-di�erentiated into neuron-like cells; however, the speci�c
protocols for inducing this di�erentiation involve toxic chemicals and thus
cannot directly be utilized within humans. As such, further research and
study of the di�erentiability of MSCs is warranted when considering their
potential as a viable therapeutic for ALS and more broadly, neuron
degeneration.

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7. Mesenchymal Stem Cell Treatment for ALS
Mesenchymal stem cells could be the potential cure for ALS not only due to 
its ability to stimulate tissue repair by di�erentiating into motor neurons 
but also by repairing damaged cells within the body. MSCs are especially 
advantageous compared to other stem cells due to many of its properties. 
One of these advantages include its great availability—they can be derived 
from adult tissue such as bone marrow tissue, skeletal tissue, or adipose (fat) 
tissue or can also be derived from fetal tissue such as the placenta or 
umbilical cord. Because of these speci�c tissue sources, MSCs can be found 
in abundance, especially due to the medical waste created from these tissues. 
For example, adipose tissue can be obtained from liposuction while the 
placenta is delivered and most of the time gotten rid of. However, bone 
marrow tissue—the soft, spongy tissue found inside the bone and contains 
stem cells62—can be obtained in the most abundance and is even possible to 
be extracted from the patient itself to mitigate the chance of rejection by the 
host.

Although MSCs are multipotent, they can exhibit pluripotent properties63. 
There is growing evidence that MSCs can transdi�erentiate into motor 
neurons. One study shows that a cocktail of basic �broblast growth factor 
(bFGF) and retinoic acid (RA) with human MSCs (hMSC) provide the 
most e�ective and e�cient transdi�erentiation of MSC into neural cells64. 
Two days after injection of these cells, these cells expressed glial markers, and 
12 days after injection, 90% of the hMSCs di�erentiated into cells that 
expressed neuronal markers, which also include transcription factors linked 
to aid the development of the di�erentiated neurons65. This con�rmed the 
ability of MSCs to be able to di�erentiate into neurons, providing a method 
to stimulate tissue repair.

After being injected intrathecally, in order for the MSCs to di�erentiate and 
develop in the correct area, ALS allows for an e�ective stimulus. A key 
advantage of MSCs over similar forms of stem cells is their ability to migrate 
towards in�ammatory foci through the expression of chemokine receptors, 
and as a pathogenetic mechanism of ALS, in�ammation provides MSCs the 
knowledge of the damaged site66. Chemokines are a family of cytokines 
which stimulate white blood cell migration to sites of infection and thus

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play an integral role in the homeostasis of the immune system67. Chemokine
receptors interact with the chemokines, themselves, in order to manage the
function of the immune system; it is thus evident that the expression of
chemokine receptors by MSCs plays a key role in the reduction of
in�ammation to maintain equilibrium within the immune system.

Figure 3. Mesenchymal stem cells are extracted from bone marrow and are intrathecally
injected into the lateral spinal cord, where they can transdifferentiate into motor neurons.

MSCs not only stimulate tissue repair by di�erentiating into motor neuron
cells but can also repair damaged cells and prevent motor neuron
degeneration from taking place to cure the disease. Human and animal
MSCs showed promising results in regard to using these stem cells for
neural repair and not just to replace the damaged motor neurons. One way
MSCs do this is by producing trophic factors, which can repair or
regenerate tissue68,69. Trophic factors are helper molecules that allow
neurons to develop and maintain connections with their neighbors. They
help establish the connection and allow motor neurons to communicate
with their target cell, skeletal muscle cells. They help maintain and support
motor neurons and also aid in repairing damaged motor neurons back to a
healthy condition23. However, although animal trials were successful in
proving the healing properties of these factors, human trials did not
produce the same success and need to be further researched due to the
factors’ inability to reach the target cell but large amounts being too
harmful.

Another way MSCs help repair damaged motor neurons is through
mitochondrial transfer. The use of mitochondrial transfer can aid in tissue
regeneration and repair, and can also restore the bioenergetic needs of
damaged cells70. This transfer primarily occurs through the formation of
intracellular nanotubes, gap junctions, and microvesicles for cell-cell

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communication. Numerous studies have demonstrated that there has been
an upregulation of mitochondrial respiration and ATP levels with a
simultaneous reduction of oxidative damage upon the culturing of MSCs
with injured tissue, indicative that mitochondrial transfer is an important
means by which cellular functions and energies can be restored.

There is also growing evidence to suggest that MSCs have anti-apoptotic
e�ects, which limits the extent of damage to improve tissue healing.
Although more research has to be done in this area, exosomes are used to
release factors that indirectly have this e�ect69. The secretion of exosomes is
an important property of ALS, which allows for the reduction of the e�ect
of pathogenetic mechanisms in order to heal damaged cells. Exosomes have
the ability to cross the blood-brain barrier, which is a unique ability and is
signi�cant for neurological disorder therapeutics/treatment. They secrete
therapeutic factors like cytokines that limit in�ammation as well as trophic
factors that help maintain brain and spinal cord connectivity to muscle cells.
Additionally, studies have shown that MSC derived exosomes mediate
angiogenesis8, and this enhancement of angiogenesis and myogenesis
promotes muscle regeneration, which is crucial for ALS treatment in which
the motor neurons are implicated.

Studies have indicated that MSCs have successfully improved the
pathological features and development of ALS and display a high level of
therapeutic plasticity7. Therefore, MSCs would be a promising cure as it
allows for di�erentiated motor neurons to replace damaged cells while also
providing mechanisms for the damaged cells to repair themselves.

8. Practical Applications
There have been numerous studies conducted regarding MSCs and their
applications as a therapeutic for ALS, many of which have o�ered a greater
insight into potential applications of MSCs in a clinical setting. Clinical
trials have indicated that MSC cells, upon their transplantation, are capable
of inducing a substantial upregulation of neurotrophic factors, some of
which include the glial-derived neurotrophic factor and the basic �broblast
growth factor. Neurotrophic factors are crucial with respect to the
consideration of potential treatments for ALS, since it has been

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demonstrated that they prolong motor neuron survival in ALS. A uni�ed
delivery of various neurotrophic factors has been shown to have a synergistic
e�ect on the pathogenesis of ALS itself, and MSCs induced with
neurotrophic growth factors are demonstrated to display protective e�ects
in many neurodegenerative disease models71.

In a similar clinical trial, a medium based MSC induction process was
devised in which MSCs were induced with neurotrophic factors, which
possessed the ability of an enhanced secretion of GDNF, VEGF (vascular
endothelial growth factor), the hepatocyte growth factor, and brain-derived
neurotrophic factors71. Upon the transplantation of these neurotrophic
factor induced MSCs, no signi�cant adverse e�ects were noted, and a higher
secretion of neurotrophic factors was observed, which directly correlated
with a substantial improvement in the monthly rate of decline of ALS
pathogenesis. Similarly, it has been found that when MSCs have been
cocultured with healthy tissues, there is a reduction in oxidative damage, an
upregulation of mitochondrial respiration (indicative of proper cellular
function and mitochondrial transfer), and an upregulation of ATP levels70.
In general, though, the practical and clinical applications of MSCs are
attributed to their di�erentiation plasticity, their capability of the secretion
of bioactive compounds as dependent on the microenvironmental
condition (playing a role in immunomodulation, reduction of
in�ammation, and regeneration), their ability to migrate to sites of injured
tissue upon intravenous injection, and their immunomodulatory
capacities72.

9. Future Directions
MSCs do present a few challenges with regard to their transplantation and
application as a reliable disease therapeutic that need to be further
researched before use. For example, challenges can arise in the
characterization of MSCs, because after they are isolated and selected, it
must be ensured that the MSCs are pure, active, undi�erentiated, and
functional for their clinical application. In addition, when MSCs are
utilized in cell delivery treatments such as in neurodegenerative disorders, it
must be ensured that the microenvironment of the host meets the
requirements of the speci�c type of cell56. Also, although MSC therapies are

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generally considered to be safe as documented in various clinical studies, the
utilization of a relatively large number of living MSCs carries certain risks,
such as occlusion within arterioles, capillaries, and venules, a transformation
of transplanted cells into inappropriate cell types such as those displaying
malignancies, and proarrhythmia. Similarly, the transplantation of living
cells with the ability to replicate is inherently high-risk, because the grafted
cells cannot be completely removed if there is an adverse response to
treatment or if the disease is ultimately resolved59.

Moreover, it has been demonstrated that the functioning of MSCs declines
with age, and this degradation of function can be implicated in the loss of
tissue integrity and homeostasis8. Interestingly, the functional activity of
MSCs typically declines during and as a consequence of cell senescence - a
mechanism through which the aging of a cell occurs and cellular replication
ceases, with an absence of cell death73. This can have a signi�cant adverse
impact on MSC function when utilized for the regeneration of injured
tissue and therefore, strategies to prevent or delay senescence must be
evaluated in order to yield a longer bene�cial impact and increased MSC
quality8.

It is relevant to note that a comprehensive study of the mechanisms of
di�erentiation of stem cells can aid in the current understanding of how the
brain and spinal cord can be individually targeted to stimulate their repair74.
Furthermore, the speci�c pathogenetic mechanisms of exosomes, and their
role in therapeutic applications through their capacity of cellular repair
should be further examined. The advantages of MSC derived
exosomes/extracellular vesicles (EV) have been elucidated in this paper; for
instance, although these EVs have demonstrated bene�cial e�ects in the
treatment of malignancies, tumor cells through EVs have the potency to
function as either tumor promoters or suppressors. Speci�cally,
MSC-derived exosomes have been reported to be involved with tumor
growth, angiogenesis, and metastasis. However, there does exist a
discrepancy between the behaviors of MSC exosomes, which may be
associated with the sources of MSCs, genotypic characteristics of tumors,
and the stages of tumor growth8. Thus, the side e�ects and implications of
MSC-derived EVs must be further investigated.

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Most signi�cantly, the protocols for inducing cellular di�erentiation into
MSCs cannot be directly incorporated within human beings due to their
incorporation of toxic chemicals75. This warrants further study into the
development of induction methods that can be safely executed within
patients. Overall, though, the mechanisms of MSCs, in addition to their
capacity as a universal therapeutic within a clinical setting for ALS and
similar degenerative diseases needs to be examined to a greater extent, in
order to gain an increased understanding of the current state and
application potential of MSCs, as well as of methods that could be
implemented to circumvent the potential risks associated with the
administration of MSCs.

10. Conclusion
Amyotrophic lateral sclerosis is a rare and progressive neurodegenerative
disease with no cure to date. While the causes of ALS remains unclear,
current theories for ALS pathogenesis include mitochondrial damage,
glutamate excitotoxicity, neuroin�ammation, and oxidative stress. Existing
treatments to slow the degeneration of motor neurons and extend survival
rates and/or time to tracheostomy include therapeutics like riluzole and
edaravone, gene therapy to target
ALS-related gene mutations, and astrocyte transplantations to reverse
neurotoxicity in the CNS. However, the mechanisms for these therapies are
also not well-understood, and they are not a long-term solution. They
mainly target one or two pathogenetic mechanisms or do not provide a
solution to treat all ALS cases, so MSC therapy may be the answer to a cure
for ALS. Mesenchymal stem cells have been shown to be a promising
therapeutic for ALS, based on preclinical and clinical trials, due to their
ability to stimulate tissue repair by di�erentiating into muscle cells as well as
providing for means to repair damaged tissue. Challenges associated with
MSC therapies such as the high risk and irreversibility deem it essential for
further research on the administration of MSC treatments for ALS.

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Con�icts of Interest
The authors declare that there is no con�ict of interest regarding the
publication of this paper.

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