REVIEW

Amyotrophic Lateral Sclerosis: An Update

for 2018
Björn Oskarsson, MD; Tania F. Gendron, PhD; and Nathan P. Staff, MD, PhD

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons and other
neuronal cells, leading to severe disability and eventually death from ventilatory failure. It has a prevalence
of 5 in 100,000, with an incidence of 1.7 per 100,000, reflecting short average survival. The pathogenesis
is incompletely understood, but defects of RNA processing and protein clearance may be fundamental.
Repeat expansions in the chromosome 9 open reading frame 72 gene (C9orf72) are the most common
known genetic cause of ALS and are seen in approximately 40% of patients with a family history and
approximately 10% of those without. No environmental risk factors are proved to be causative, but many
have been proposed, including military service. The diagnosis of ALS rests on a history of painless
progressive weakness coupled with examination findings of upper and lower motor dysfunction. No
diagnostic test is yet available, but electromyography and genetic tests can support the diagnosis. Care for
patients is best provided by a multidisciplinary team, and most interventions are directed at managing
symptoms. Two medications with modest benefits have Food and Drug Administration approval for the
treatment of ALS: riluzole, a glutamate receptor antagonist, and, new in 2017, edaravone, a free radical
scavenger. Many other encouraging treatment strategies are being explored in clinical trials for ALS; herein
we review stem cell and antisense oligonucleotide gene therapies.
ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2018;nn(n):1-12

From the Department of

A
myotrophic lateral sclerosis (ALS) is a contribute to mortality more so than the
Neurology (B.O.) and
fatal neurodegenerative disorder that, features caused by the loss of upper motor Department of Neurosci-
by definition, affects lower and upper neurons in the brain, which include spasticity, ence (T.F.G.), Mayo Clinic,
motor neurons. In the United States, the clumsiness, brisk reflexes, and functional Jacksonville, FL; and
Department of
disease is often referred to as Lou Gehrig’s limitations. It is now appreciated that extramotor Neurology, Mayo Clinic,
disease after the New York Yankee baseball systems are also involved in ALS, albeit to vary- Rochester, MN (N.P.S.).
player who was diagnosed as having ALS in ing degrees. For example, some patients develop
1939 at Mayo Clinic. In addition to motor neu- neuronal loss in the frontotemporal cortex, with
rons, neurons in the frontal cortex and other approximately half of all patients experiencing
neuroanatomical regions may also be affected. cognitive and behavioral signs or symptoms.
This review covers our current understanding The recognition of extramotor involvement in
of the disease process, its epidemiology, the cur- ALS, which was previously overlooked, has
rent standard of care, a new Food and Drug improved clinical care and provided new insight
Administration (FDA)eapproved therapy, and into the pathogenesis of ALS.
select potential future therapies.

EPIDEMIOLOGY
BACKGROUND The US National ALS Registry Act was enacted
Amyotrophic lateral sclerosis was described in in 2008 by Congress to gather and organize
1869 by the great French neurologist Charcot information about who gets ALS and its poten-
as a neurodegenerative disorder that affects tial causes; such data have now been collected
lower and upper motor neurons (Figure 1).1 for 6 years. This unique program, adminis-
Loss of lower motor neurons, which extend tered by the Agency for Toxic Substances
from the spinal cord to the muscles, leads to and Disease Registry, captures information
muscle weakness, wasting, cramps, and fascicu- from 4 national administrative databases (the
lations. These lower motor neuron features Centers for Medicare and Medicaid Services,

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 MAYO CLINIC PROCEEDINGS

may carry several hundreds or thousands of

ARTICLE HIGHLIGHTS repeats. Of note, C9orf72 repeat expansions
are frequently associated with cognitive and
d No diagnostic test for amyotrophic lateral sclerosis (ALS) is yet
behavioral changes. Together with the
available. C9orf72 repeat expansion, mutations in genes
d The prevalence of ALS in the United States is 5 in 100,000. encoding copper-zinc superoxide dismutase
d Care for ALS is best delivered through a multidisciplinary ALS (SOD1), transactive response DNA-binding
clinic. protein 43 (TDP-43), and fused in sarcoma
(FUS) account for more than 50% of the famil-
d A new intravenous medication, edaravone, was approved for ial ALS cases, and another 30 or so genes have
the treatment of ALS in 2017. been identified as possibly causing ALS,
d Edaravone slows disease progression by 33% (measured by the increasing the risk of developing ALS, or
ALS Functional Rating Scale-Revised) in a very select population hastening disease progression. For example,
of patients with ALS. the Ala4Val variant in the SOD1 gene causes
a highly aggressive disease phenotype, and
mutations in FUS are associated with a
younger onset of disease and rapid disease
the Veterans Health Administration, and the
progression. It has also been suggested that
Veterans Benefits Administration), and also
some genetic variants influence the response
lets people self-identify as patients with ALS
to therapy and may, thus, lead the way to
and provide additional information through
precision medicine for ALS.7
a voluntary online enrollment system. The
Although our understanding of the genetic
program has substantially added to our overall
basis of ALS is continually expanding, our
knowledge about the epidemiology of ALS,
knowledge of other risk factors is less advanced.
and it estimates an ALS prevalence rate in
Given that genetic causes for ALS are deter-
the United States of 5 cases per 100,000 pop-
mined at conception but ALS develops most
ulation for 2013, the last year for which pub-
often in adulthood, other factors, such as time
lished data are available.2 This is consistent
and environmental exposures, must underpin
with most previous estimates, including one
or influence disease susceptibility. The relation-
for Olmsted County in Minnesota, where an
ships among genetic risk, environmental
average annual incidence rate of 1.7 cases
factors, and disease phenotype, however,
per 100,000 people was seen.3 According to
remain largely unknown. One reason for this
population-based studies, the median survival
is that environmental risk factors for ALS have
of patients with ALS is 2 to 3 years from symp-
proved difficult to identify, in part because
tom onset, with death typically resulting from
exposure to such factors can change over time
ventilatory failure. Amyotrophic lateral scle-
and may not be accurately recorded. Nonethe-
rosis is more common in men than in women
less, although there are currently no known
by a factor of 1.5, and the rate of disease pro-
environmental risk factors that irrefutably link
gression may be more rapid in patients with an
to ALS, suspected risk factors include smoking,
older age at onset, a bulbar site of onset, cogni-
athletic propensity or activity, military service,
tive impairment, and certain genotypes.4
b-N-methylamino-L-alanine, head trauma,
Regarding the latter, approximately 10% of
electromagnetic fields, agricultural chemicals,
ALS is familial and caused by a genetic muta-
and exposure to lead and other heavy metals.8
tion that is usually inherited in a mendelian
Overall, the gene-time-environment model
autosomal dominant manner. A hexanucleo-
suggests that the development of ALS is a multi-
tide G4C2 repeat expansion in the chromo-
step process in which genetic defects are but 1
some 9 open reading frame 72 gene
of several steps eventually leading to ALS.4
(C9orf72) is the most common known genetic
cause of ALS, accounting for 30% to 40% of
familial ALS, and it also causes frontotemporal PATHOGENESIS
dementia (FTD).5,6 Whereas the normal range Although the pathogenesis of ALS remains
of G4C2 repeats is generally considered to be largely unknown, neuropathologic features
30 or fewer, patients with either ALS or FTD and gene mutations associated with ALS

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AMYOTROPHIC LATERAL SCLEROSIS 2018

have shed important light on the etiology of

the disease. Indeed, we have dramatically
advanced our understanding of the pathogen-
esis of ALS in the past decade, which has led
to optimism in the field. A common feature
of many neurodegenerative diseases character-
ized by neuronal dysfunction and eventual cell
death is the accumulation of proteinaceous ag-
gregates in cells throughout the nervous sys-
tem. A protein called TDP-43 is the primary
component of such aggregates in most ALS
cases, including cases caused by C9orf72
repeat expansions.9,10 Notably, mutations in
TARDBP, the gene that encodes the TDP-43
protein, have been discovered in sporadic
and familial ALS, providing a direct link
between TDP-43 abnormalities and neurode-
generation.11-21 How these abnormalities in
TDP-43 cause neuronal loss is not yet
definitely known but is likely to involve a
combination of events. The TDP-43 inclusions
may themselves be toxic, and they may also
harm neurons by sequestering TDP-43 and
preventing it from performing its usual
functions in cells.22,23
Transactive response DNA-binding protein
43 is an RNA-binding protein with more than
6000 RNA targets in the brain; combined with
its role in multiple steps of RNA processing,
this suggests that disrupted RNA metabolism
contributes to ALS pathogenesis. Further
supporting this notion is the fact that mutations FIGURE 1. The primary motor system showing connections among upper
in FUS, heterogeneous nuclear ribonucleoproteins motor neurons, lower motor neurons, and the muscle effector organ.
A1 and A2B1, TATA-box binding protein associated
factor 15, and TIA1, which also encode RNA-
binding proteins, are implicated in the causation proper stress granule dynamics and thus
of ALS.24 Through functions performed in prevent a proper stress response. For example,
both the nucleus and the cytoplasm, these TIA1 mutations delay stress granule disassembly
RNA-binding proteins determine the fate of after stress and promote the accumulation of
RNA transcripts from their maturation to their stress granules that harbor TDP-43.24 Indeed,
degradation. One such critical function is the it bears mentioning that the localization of
recruitment of messenger RNA (mRNA) tran- TDP-43 and related RNA-binding proteins to
scripts into stress granules formed on cellular stress granules may further promote their
stress; this facilitates cell survival by silencing aggregation and the disruption of neuronal
mRNAs not needed to cope with the stress while homeostasis. Of interest, in patients with ALS
allowing the optimal translation of mRNAs that caused by C9orf72 repeat expansions, TDP-43
are.25 Stress granules are membraneless, cyto- pathology is accompanied by other hallmark fea-
plasmic organelles composed of mRNAs, trans- tures that are also believed to contribute to
lation initiation factors, 40S ribosomes, and impaired RNA metabolism and stress granule
RNA-binding proteins.26 Once the stressful dysregulation. One such feature is the accumula-
event has subsided, stress granules disassemble. tion of repeat-containing RNA transcribed from
However, perturbations in TDP-43, FUS, TIA1, C9orf72 repeat expansions, which binds to
and related RNA-binding proteins can impair various RNA-binding proteins and, in so

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TABLE. Diseases Commonly Considered in the Differential Diagnosis of Amyotrophic Lateral Sclerosis
Upper motor neuron
Region/involvement suspect findings Lower motor neuron suspect findings
Bulbar Brainstem lesion (stroke, multiple Brainstem lesion (stroke, multiple sclerosis,
sclerosis, tumor) tumor), neuromuscular junction disorder
(myasthenia gravis, muscle-specific tyrosine
kinase myasthenia), bulbospinal muscular
atrophy
Cervical Cervical myelopathy Multifocal motor neuropathy, cervical
radiculopathy
Lumbosacral Thoracic myelopathy Lumbosacral radiculopathy

doing, can impair their function. Furthermore, a of neurons, but also involves, and possibly
variety of aggregation-prone proteins of even requires, other cell types, including astro-
repeating dipeptides are produced from cytes, microglia, macrophages, and potentially
C9orf72 repeat expansions, and 2 of oligodendrocytes.44-47 Also of note, for most
thesedpoly(GR) and poly(PR)dtrigger stress patients with ALS, the disease has a focal site
granule formation or impair their dynamics.27-30 of onset that then spreads along neuroanatom-
In addition to defects in RNA metabolism, ical pathways, possibly suggesting a prion-like
impaired protein metabolism is thought to transmission to susceptible tissues.48,49
contribute to ALS pathogenesis.31 Indeed, muta- Finally, the concept of ALS as a single
tions in genes involved in protein clearance, such disease has also been challenged. As described
as charged multivesicular body protein 2B, opti- herein, there are many genetic variants and
neurin, sequestosome 1, valosin-containing pro- perhaps environmental risk factors that can
tein, TANK-binding kinase 1, and ubiquilin 2, lead to the overlapping clinical phenotypes of
cause ALS or FTD.32-39 There exists 2 major pro- upper motor neuron disease, lower motor
tein degradation pathways in cells: the ubiquitin neuron disease, and even FTD, which are likely
proteasome system, which degrades short-lived, to cause ALS through both common and
soluble proteins, and the autophagy-lysosome distinct pathologic mechanisms. Indeed, it has
pathway, which degrades relatively long-lived been speculated that many clinical trials in
proteins, misfolded and aggregated proteins, ALS have failed, at least in part, due to potential
and organelles. Defects in these degradation sys- differences in underlying pathophysiologic
tems may not only contribute to the aberrant mechanisms among patients with ALS. A better
accumulation of TDP-43, FUS, or SOD1 but understanding of the molecular underpinnings
also further compound the problem by failing of the various putative forms of ALS and the
to clear stress granules and, thus, promote the development of representative preclinical
aggregation of these proteins.40 In turn, the pro- models are expected to facilitate endeavors to
tein aggregates are proposed to inhibit protein identify effective treatments for ALS.
degradation pathways and to sequester RNA
and other proteins required for proper cellular CLINICAL CARE
function. In addition, in C9orf72-associated Amyotrophic lateral sclerosis remains a disease
ALS, dipeptide repeat proteins also bind proteins without a specific diagnostic test. A clinical
involved in key cellular pathways and adversely diagnosis of ALS is based on a history of
affect protein translation and degradation.41,42 progressive, painless weakness, and examina-
Many additional pathologic mechanisms tion findings of both upper and lower motor
have been implicated in various steps of the neuron dysfunction. The initial symptoms of
neurodegenerative process of ALS, including ALS vary among patients depending on the
mitochondrial dysfunction, oxidative damage, degree of upper and lower motor neuron
excitotoxicity, inflammation, and defects in involvement and which regions of the body
intracellular and nucleocytoplasmic trans- are involved. Where the neurologic deficits
port.43 Further adding to the complexity of manifest dictates which other diseases may
the disease is that ALS is not only a disorder produce the observed symptoms and, thus,
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informs the differential diagnostic evaluation.

Clinical presentations can range from a spastic
pattern of speech caused by upper motor
neuron loss to a foot drop caused by lower
motor neuron loss, with numerous permuta-
tions in between (diseases commonly worth
considering are listed in the Table). The diag-
nosis may, therefore, be uncertain initially,
and only with the development of additional
features can the diagnosis be established with
greater certainty. The appropriate exclusion
of other diseases in the differential diagnosis
is paramount, and electrophysiologic evalua-
tions (electromyography and nerve conduc-
tion studies) are often the most important
tests to help establish a diagnosis, but neuroi-
maging and serologic studies can also be of
great value and are indicated in most cases.
Spinal fluid analysis and nerve and muscle bi-
opsies are tests that only rarely need to be used
to exclude specific diseases in the differential
diagnosis.
The standard of care for ALS is delineated in
the 2009 American Academy of Neurology
practice parameter, and several other organiza-
tions provide guidance, including the 2012 Eu-
ropean Federation of the Neurological Societies
Task Force and the United Kingdom’s National
Institute for Health and Care Excellence, with
its more recent 2016 guidelines for ALS
care.50-53 There exist differences among the
guidelines accounting for new evidence and FIGURE 2. Illustration of symptoms that can be addressed in amyotrophic
lateral sclerosis.
data that emerged since their respective publi-
cation, and there are also methodological differ-
ences. For example, the American practice
parameter is more stringent and avoids making Until recently, disease-modifying therapies
recommendations if high-quality evidence is for ALS have been limited to riluzole, a
lacking, whereas the other guidance documents glutamate release inhibitor approved for the
provide expert-based recommendations. treatment of ALS in 1995. The drug is gener-
Another difference is the scope of the guidance, ally well-tolerated, but has a limited potency.
and the National Institute for Health and Care A survival benefit of approximately 3 months
Excellence guideline, which is more encom- was noted in clinical trials.57,58 No effect on
passing, recommends that physicians make function or quality of life was discernible.
prompt referrals to Neurology before patient Attempts at identifying subgroups of patients
diagnosis, and subsequently emphasizes inte- more likely to benefit from riluzole treatment
gration with primary care providers (general have been made.59 Many patients use comple-
practitioners). All recommendations focus on mentary and alternative therapies exemplified
a multidisciplinary approach for the care of pa- by vitamins and nutritional supplements.60
tients with ALS; this has proved to be effective, Some supplements have scientific rationale,
but this model of care may not be fully reim- but there is insufficient clinical trial evidence
bursed in the United States.54,55 Telemedicine to substantiate such claims. Counseling to
is emerging as a complement to the current avoid the use of dangerous treatments is
center-based care model.56 advisable.

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With the limited potency of disease- Ventilatory failure is the leading cause of
modifying agents, management instead centers death in patients with ALS. Pulmonary function
on addressing symptoms (Figure 2). This testing, nocturnal pulse oximetry, and reported
includes cognitive and behavioral evaluations symptoms can help gauge the progression of
given that thinking and behavioral symptoms breathing weakness. Assisted ventilation, typi-
are increasingly recognized in patients with cally with noninvasive bilevel positive airway
ALS, and this can impact disease course, pressure settings, can substantially prolong life
symptom management, and decision making and also help improve quality of life.72,73 The
throughout the illness.61 Clinical interventions trend in recent years has been to use volume-
are more difficult for patients with cognitive controlled modes instead of pressure control
impairment to accept, but special strategies, based on the notion and emerging evidence
such as additional education and recurrent that this is better tolerated and more effec-
reminders, may help improve compliance. tive.74,75 These modes of ventilation can be
Unfortunately, no medications for cognitive delivered by machines with differing complexity.
and behavioral dysfunction are of clear benefit, The US Centers for Medicare and Medicaid Ser-
including cholinesterase inhibitors, which are vices cover the necessary respiratory therapy
used in amnestic dementia. support only for more complex devices and
Approximately 25% to 50% of patients also do not require as extensive documentation
with ALS develop pseudobulbar affect.62 This for more advanced devices. Noninvasive ventila-
neurologic condition, also known more tion often eventually fails, thus necessitating a
descriptively as inappropriate emotional expres- decision about proceeding with an invasive
sion disorder, is characterized by a tendency to interface (eg, tracheostomy). Only a small mi-
cry or laugh uncontrollably or out of propor- nority of patients with ALS in the United States
tion to the experienced emotion.63 These out- select this option, with physician and caregiver
bursts may be mood incongruent, with preferences likely being important factors in
sadness manifesting as laughter, or joy mani- this decision.76 Both patients and caregivers
festing as crying. Several medications, should be provided with information regarding
including a combination of dextromethorphan the consequences of invasive ventilation to allow
and quinidine, can be effective in controlling them to make educated decisions based on their
the symptom.64 This combination was FDA own needs and goals. Not implementing timely
approved for the treatment of pseudobulbar tracheostomy can lead to a preventable death,
affect in 2010. An ALS diagnosis is a major and an emergency tracheostomy performed
psychological stressor, and although depres- without a good understanding of the long-term
sion and anxiety are not necessarily more outcome can also have negative consequences.
common in the ALS population compared Strategies to maintain lung compliance and
with the general population, depression and help airway clearance are also recommended.77
hopelessness are likely negative prognostic Drugs known to reduce respiratory drive, such
factors for ALS and should, thus, be treated as opiates and benzodiazepines, should be
if present.65,66 Counseling and peer support avoided, if possible, until the terminal stage of
groups for patients and caregivers are often the disease. Phrenic nerve stimulators, also
valued. Fatigue is another common symptom known as diaphragm pacers, are not effective
that has been treated successfully with stimu- in ALS.78,79 Loss of voice function can artificially
lants, and contributing respiratory problems be compensated for with speech-generating
should be addressed.67 Although ALS is devices and less complex writing boards.
thought to be painless, nonneuropathic pain Impaired swallowing can lead to aspiration
is experienced by most patients.68 Pain is often and poor nutrition. Amyotrophic lateral
due to secondary joint and back issues and sclerosis leads to increased calorie needs, and
needs to be managed according to its origin. weight loss correlates with shorter survival.80,81
Muscle cramps affect most patients with ALS Low vitamin D levels are seen in ALS, but recent
and can be painful. Mexiletine is emerging as studies suggest that vitamin D is not an
a possible treatment and as an alternative to independent prognostic marker.82,83 Safe swal-
quinine, which is no longer recommended lowing techniques and diet modifications can
by the FDA for clinical use.69-71 prolong functional independence. Gastrostomy
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AMYOTROPHIC LATERAL SCLEROSIS 2018

placement is the standard accepted treatment to can be described as peaceful, and terminal anxi-
ensure adequate nutrition, but it may or may ety and shortness of breath are controlled with
not prolong survival or be beneficial outside oxygen, opiates, and benzodiazepines.91 Infor-
of providing a way to deliver nutrition, hydra- mation regarding hospice care and how terminal
tion, and medications.84,85 For patients on symptoms can be effectively managed should be
continuous ventilatory support it would seem provided when appropriate. Patients often have
likely that gastrostomy feeding is required to questions regarding physician-assisted suicide,
achieve the full benefit of the ventilatory treat- which is now legal in many states. This remains
ment. Sialorrhea (hypersalivation) due to a complex ethical and legal question, but the
impaired swallowing can be managed with anti- acceptance of active suicide as an appropriate
cholinergic medications, salivary gland botuli- option to death from untreated ventilatory weak-
num toxin injections, or radiotherapy.86,87 ness is growing. Most patients with ALS do not
Suction machines can be used to remove oral use this option even in states where it is legal,
and pharyngeal secretions. Thick secretions and a small minority of patients with ALS do
can be liquefied with hydration, oral muco- commit suicide even without physician assis-
lytics, or nebulized acetylcysteine. tance.92 Cognitive impairment accompanied by
Many devices can be used to preserve func- difficulties making decisions and grasping
tional independence; some of the most complex problems can make these types of
commonly prescribed devices are ankle-foot discussions even more difficult.
braces, walkers, wheelchairs, hospital beds, toi-
leting equipment, and lifts.88 Physical and NEWLY APPROVED THERAPY
occupational therapy can maximize the benefit Edaravone is an intravenous drug for the
of equipment and provide range of motion and treatment of ALS that was approved by the
exercise programs to retain function and mini- FDA in May 2017, approximately 2 years after
mize pain. Spasticity is an upper motor neuron its approval for the treatment of ALS in Japan
symptom that can cause pain and limit func- and South Korea. As of December 2017, the
tion, but occasionally it provides a degree of drug has not been filed for approval in Europe,
functional benefit by allowing patients to do and the European ALS investigators in the Euro-
pivot transfers or other activities where a stiff pean Network to Cure ALS recommend addi-
limb is more useful than a flaccid one. Baclofen tional studies before a European approval.93
and other oral muscle relaxers are the mainstay Edaravone was first approved in Japan in
of treatment, but botulinum toxin injections 2001 for the treatment of cerebrovascular
and, for the rare patient, implanted baclofen accidents, and it has been dosed in more than
pumps are also useful.89 Constipation is a 1.7 million patients. The use of this drug, a
frequent problem in ALS; bowel regimen strate- free radical scavenger, was subsequently
gies, such as fluid, fiber, and laxative drugs, assessed for other neurologic disorders,
help manage the symptom.90 Urinary urgency including ALS, in several clinical trials. In one
is another symptom that can be managed with trial, 139 patients with ALS were randomized
anticholinergics and intravesical botulinum 1:1 to receive active or control intervention
toxin.90 It is unclear whether these latter symp- over a 6-month duration.94 This short duration
toms are purely secondary to immobility or are did not allow for the assessment of an effect on
due to ALS involvement of the autonomic survival, and neither was one seen in this study.
nervous system.90 The selection criteria were also narrow and
The patients’ individual goals of care are somewhat innovative with the purpose of
important, and treatment plans should be enriching for patient groups that seemed to
tailored with these goals in mind and using perform better in a previous study.95 The
interventions acceptable to the patient. Most pa- main inclusion criteria were age 20 to 75 years,
tients with ALS will die of their ALS, and many a Japan ALS Severity Classification of grade 1 or
will have questions regarding this process. 2 (no to mild disability), scores of at least 2
Should the patient want this type of information, points on all 12 items of the ALS Functional
factual and compassionate information Rating Scale-Revised (ALSFRS-R), forced vital
regarding the dying process can help demystify capacity of 80% or more, definite or probable
it and reduce anxiety. For most patients, death ALS according to the revised El Escorial criteria,

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 MAYO CLINIC PROCEEDINGS

and disease duration of 2 years or less. In addi- need, lack of highly effective therapies, rapid
tion, during a 12-week lead-in phase, patients disease course, engaged patient community,
had to lose 1 to 4 points on the ALSFRS-R and well-developed research infrastructure
before being randomized. It is estimated that are likely factors contributing to this. The
approximately 1 in 20 patients with ALS lack of biomarkers of the disease is likely the
followed at an ALS clinic would meet these most limiting factor for treatment develop-
enrollment criteria, which has raised questions ment at this time, but many approaches are
regarding the generalizability of the results. being explored to rectify this deficiency.
Nevertheless, the results were rather remark-
able, showing a slowing in the decline of the Stem Cells
ALSFRS-R score by 33% over the 6 months. During the past few years, there has been
The ALS quality-of-life measures also tracked considerable excitement about stem
accordingly showing a significantly slower cellebased therapies for ALS and other neuro-
decline. Respiratory measures trended in the degenerative diseases. Stem cell therapeutics
same direction but did not reach statistical are now in phase 1, 2, and even 3 clinical trials
significance. and use a variety of cell types. Current stem cell
Edaravone is delivered by intravenous approaches are primarily designed to help
infusions in cycles consisting of daily dosing protect surviving motor neurons via paracrine
for 2 weeks followed by a 2-week drug-free effects (neuroprotection); they are not designed
period. Subsequent infusion cycles allow inter- to replace dead motor neurons.
ruptions over the weekend. The drug’s half-life Mesenchymal stromal cells (MSCs) are pri-
is approximately 4.5 to 6.0 hours, suggesting marily being used as an autologous stem cell
that a more frequent dosing schedule could therapy for ALS due to their ability to secrete
be more beneficial. Most patients in the neurotrophic factors and modulate the immune
studies were taking concomitant riluzole, and system, 2 mechanisms shown to slow disease
the 2 medications can be used together. The course in animal models. The MSCs naturally
drug’s safety profile is favorable, with more pa- arise from pericytes in several tissue types (fat,
tients in the placebo arm having significant connective tissue, bone marrow, dental pulp)
adverse events compared with patients and are thought to mediate tissue healing while
receiving drug in the Japanese trial; this has also being able to differentiate into bone, carti-
also been observed in the author’s clinical lage, and fat.97,98 The MSCs are isolated from
experience in the United States to date. fat or bone marrow biopsies, expanded
Allergic reactions, including anaphylaxis, are in vitro, and then injected into the thecal space
the most severe reported reactions. Edaravone via lumbar puncture (with or without simulta-
does not have any listed drug interactions, and neous intravenous or intramuscular injections)
its dosing is not recommended to be adjusted or directly intraspinally.99-102 Some groups
for moderate kidney or liver dysfunction. The have also developed conditioned media that in-
cost of the medication and the frequent creases the MSCs’ neurotrophic factor secretion,
infusions has further increased the cost of and others are using genetic editing strategies to
ALS care in the United States. Many insurance increase the secretion of specific factors.103,104
companies and the Veterans Health Adminis- Overall, the safety profile of MSC therapies has
tration limit the coverage of the drug and do been good, and the lack of required concomitant
not provide coverage for all patients with immunosuppression has been considered a
ALS. As part of its approval of edaravone, benefit. Although none of these early-phase
the FDA has requested additional studies to studies have been powered to prove efficacy,
assess the effect of more frequent and higher there have been reports of subjective benefits
dosing.96 Edaravone is also being developed and case studies that suggest that a subset of
in oral form, which would circumvent the patients may respond to therapy.99,105 A phase
major hurdles with its administration. 3 clinical trial was recently started using intra-
thecal delivery of autologous MSCs overexpress-
FUTURE THERAPIES ing neurotrophic factors.106
Currently, there are many trials of varying Another stem cell strategy uses neuroglial-
phases in ALS. The severity of the medical lineage precursors to treat ALS. With this
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AMYOTROPHIC LATERAL SCLEROSIS 2018

approach, stem cell lines have been developed strategy has mitigated many of the adverse
from fetal neural tissue, which are then events associated with repeat RNA in mouse
injected directly into the anterior horn of the models of C9orf72-associated ALS.115,116
spinal cord.107,108 Because the cells are alloge-
neic, immunosuppression is required to
prevent transplant rejection. Phase 1 and 2 CONCLUSION
clinical trials have been completed using Amyotrophic lateral sclerosis remains a fatal
stem cells obtained from human fetus spinal neurodegenerative disease destroying the pri-
tissue.109 Although not powered for efficacy, mary motor system, and it also often affects
there seemed to be modest benefit in a subset neuroanatomical regions involved in cognition
of patients, and larger multicenter trials are be- and behavior. Identifiable genetic causes, which
ing planned. Phase 1 and 2 studies using are potential drug targets, are responsible for a
similar strategies are beginning at other centers portion of sporadic cases and most cases with a
in the United States.107,110,111 positive family history, admittedly leaving most
cases without a clearly defined etiology. Never-
Other Agents theless, significant advances have been made in
At present, many agents are being investigated elucidating the pathogenesis of ALS. With an
for the treatment of ALS. One agent, the increased understanding of these pathologic
tyrosine kinase inhibitor masitinib, was filed mechanisms, we hope to be informed of the
for approval in Europe after positive yet environmental factors that may play an impor-
unpublished studies.112,113 The purported tant role. Two medications, riluzole and the
effect of the drug would be in the range of recently approved edaravone, have proved effec-
riluzole or edaravone. Additional studies may tive for the treatment of ALS, but more treat-
be required to validate the results before any ments are needed. Current treatment strategies
approvals are granted. are otherwise largely palliative, aiming to provide
The knowledge that genetic variants cause better life quality and longer survival, with assis-
ALS provides putative targets for therapy even ted ventilation being the single most powerful
in the absence of a definitive understanding of approach. With a better understanding of the
the pathologic mechanisms initiated by the underlying genetic causes and the pathogenesis
mutated gene. Directly altering the expression of ALS, many novel treatment approaches are
of the mutated gene may mitigate critical steps in development, hopefully leading to more effec-
in the development of disease. In a phase 1 tive treatments in the near future.
clinical trial, intrathecal delivery of antisense
oligonucleotides designed to inhibit SOD1 Abbreviations and Acronyms: ALS = amyotrophic lateral
expression were found to be well-tolerated sclerosis; ALSFRS-R = ALS Functional Rating Scale-Revised;
by patients with SOD1 familial ALS, and a sec- C9orf72 = chromosome 9 open reading frame 72; FDA =
ond trial is ongoing.114 Likewise, the discovery Food and Drug Administration; FTD = frontotemporal de-
mentia; FUS = fused in sarcoma; mRNA = messenger RNA;
of C9orf72 repeat expansions as a cause of ALS MSC = mesenchymal stromal cell; SOD1 = copper-zinc
uncovered a therapeutic strategy for this more superoxide dismutase; TDP-43 = transactive response
common form of ALS. As mentioned previ- DNA-binding protein 43
ously herein, many of the adverse events
Potential Competing Interests: B Oskarsson serves as a
resulting from this mutation are believed to consultant for FlexPharma and has provided consultations
arise from the accumulation of repeat- to Biogen regarding SMA. The rest of the authors report
containing RNA transcribed from the C9orf72 no competing interests.
repeat expansion. For example, these RNA
Correspondence: Address to Björn Oskarsson, MD,
transcripts aberrantly interact with RNA- Department of Neurology, Mayo Clinic, 4500 San Pablo
binding proteins and also serve as templates Rd, Jacksonville, FL 32224 ([email protected]).
for the synthesis of dipeptide repeat proteins,
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