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Amyotrophic lateral sclerosis: clinical perspectives

Authors Haringer V, Gibson S

Received 9 January 2015

Accepted for publication 19 February 2015

Published 15 April 2015 Volume 2015:5 Pages 19—31


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Lise Aagaard

Verena C Haringer, Summer B Gibson

Clinical Neurosciences Center, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. It is a rapidly advancing neurodegenerative disease leading to progressive paralysis and death, with a mean time of survival from onset of symptoms to death of 2–5 years. The pathophysiology of ALS remains poorly understood. The only US Food and Drug Administration–approved therapy for ALS is riluzole, a glutamatergic neurotransmission inhibitor, with modest benefits on survival. Many other agents have shown promising results in preclinical trials, but have yet to show benefit in human clinical trials. This review gives an overview of drugs that have been studied in clinical trials and their reported outcomes. This also includes more recent treatment strategies, including antisense oligonucleotides (ASOs) and stem cells. ASOs have the potential to target genes known to cause ALS by silencing their function. Many clinical trials are under way using these therapies. Different kinds of stem cells have been used in an attempt to either replace the lost motor neurons or to improve their metabolic supply and thus prolong their death. Given the limited therapeutic treatment options to date, the most important approach to improve the patient's quality of life remains symptom-based management. Additionally, we give an overview of the current treatment offered in multidisciplinary clinics.

Keywords: motor neuron disease, symptom management, treatment and experimental therapies, stem cells, antisense oligonucleotides, clinical trials


Amyotrophic lateral sclerosis (ALS) is a fatal disease in which the upper and lower motor neurons degenerate, leading to progressive muscle weakness and eventual respiratory failure. The incidence of ALS is about 2 in 100,000.1 It generally progresses rapidly, with a mean survival time of 2–5 years following symptom onset.2,3 The clinical hallmark of the disease is death of the motor neurons leading to muscular atrophy, muscular weakness, dysarthria, and fasciculations as well as clinical findings of hyperreflexia and spasticity. The symptoms typically manifest as focal weakness in one limb; however, one-third of the cases have a bulbar presentation resulting in dysarthria, dysphagia, and respiratory dysfunction.4 About half the affected patient population will develop frontotemporal lobe dysfunction with cognitive and behavioral abnormalities and pseudobulbar affect; a subgroup of these will go on and fulfill diagnostic criteria for frontotemporal dementia (FTD).5 As there is significant overlap in the pathogenesis and genetics of FTD and ALS,6 there is growing belief that these two diseases are different phenotypes of an ALS–FTD spectrum disorder.7

It is known that the pathogenesis of ALS has a genetic component.3 While most cases of ALS are sporadic, approximately 10% of cases report a family history of ALS.8 Currently, about 68% of ALS patients with a family history of ALS (aka familial ALS) and 11% of ALS patients without a known family history of ALS (aka sporadic ALS) have an identifiable genetic cause.3 The first ALS mutation, Superoxide dismutase-1 (SOD1), was discovered in 1993,9 and since then, many additional genes have been found. Mutations in SOD1 account for 10%–20% of familial ALS cases, and to date, >155 mutations have been identified.10 Two genes that play a role in the pathological findings of ALS are TAR DNA binding protein (TARDBP)11 and fused in sarcoma (FUS),12 which account for ~5% of familial ALS cases. The GGGGCC hexanucleotide expansion of C9orf72 is a common cause of FTD and ALS.13 This mutation is the most common known cause of both sporadic and familial ALS, responsible for about 7% of all ALS cases in the Caucasian population.14 Mutations of many other genes have been reported, but the genetic cause of about 32% cases of familial ALS and the majority of sporadic ALS continue to be unknown.3

The pathophysiology of this devastating disease remains unclear. The pathological finding of ubiquitinated TDP-43 aggregates is found in patients who carry a mutation in the TDP-43 gene (TARDBP), as well as in ALS patients without this mutation,11,15 except in cases caused by SOD1 or FUS mutations. Similar TDP-43 aggregates are also found in FTD, leading to speculation that both diseases are variations of a spectrum of TDP-43–associated disorders.16 Although TDP-43 pathology is common to most ALS cases, the pathomechanism causing this disease is unknown. Potential contributing factors include mitochondrial dysfunction, neuroinflammation, and oxidative stress. Additionally, glutamate toxicity is thought to play a role, because ALS patients have higher levels of glutamate in serum and cerebral spinal fluid (CSF) compared to healthy controls.17

Disease-modifying treatment

US Food and Drug Administration–approved treatment

Riluzole has several targets, although its proposed mechanism is as a glutaminergic neurotransmission inhibitor. It remains the only US Food and Drug Administration (FDA)–approved therapy for ALS that affects survival. Randomized trials show modest improvement in survival, possibly greater in patients with bulbar onset.18 It is likely that riluzole has less effect in advanced stage disease.19 A recent meta-analysis of all randomized controlled trials confirmed the modest increase in median survival of 2–3 months and a modest impact on functional measures.20 Given the relatively short duration of these randomized studies (≤18 months), an analysis of ALS databases over a 5- to 10-year period was initiated, for which data are suggestive of a greater long-term improvement in survival, ranging from 6 up to over 21 months.20 Given these longer studies were not randomized, these results must be interpreted with caution.

Drugs in clinical trials

Over the past decades, a multitude of experimental pharmaceutical therapies were shown to delay disease progression in ALS animal models but failed to show efficacy in clinical trials or are still in Phase I–III trials. The mechanisms of these agents include antioxidants, neuroprotection, promotion of growth factors, antiglutamate, induction of heat shock proteins, anti-inflammatory, mitochondrial-protective agents, maintenance of muscle, and reduction of SOD1. Several drugs that have been FDA-approved for other indications are currently in clinical trials for ALS, including rasagiline, fingolimod, anakinra, and tamoxifen ( Of the agents that have completed clinical trials, none have been able to significantly modify disease progression or increase survival in humans with ALS (Table 1). The failure to translate from animals to humans is at least in part due to inherent limitations when using animal models to study human diseases. There are metabolic, anatomic, and cellular differences between humans and other organisms, laboratory animals are often heavily inbred, and negative study results are often not published leading to bias. Additionally, animal models often do not accurately mimic human disease.21 The most frequently used animal model to study ALS has been transgenic SOD1G93A rodents, which have multiple copies of the human coding sequence for SOD1 with the G93A mutation.22 While this model appears to be a mimic of human ALS due to SOD1 mutations, it is unclear if the results from these rodents can be applied to non-SOD1 cases of ALS. Additional rodent models of ALS are currently being studied including TDP-43 mediated,23 which have the potential to be relevant for the majority of ALS cases.

Table 1 Summary of human clinical trial results of agents delaying disease progression in ALS animal models
Notes: Phase I clinical trial: Screening for safety in a small group of patients. Phase II clinical trial: Establishing the efficacy of the drug, usually against a placebo in a larger group of patients. Phase III clinical trial: Final confirmation of safety and efficacy in comparison to commonly used treatment.
Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS-R, ALS functioning rating scale–revised; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor; SOD1, superoxide dismutase-1.

Antisense oligonucleotides

Mutations in SOD1, associated with 10%–20% of familial ALS cases, cause the protein to misfold, leading to toxic effects on the cellular degradation machinery and formation and accumulation of SOD1 protein aggregates.10 This results in a cellular stress response and eventual cell death, although the exact mechanism is unknown.10,24 Reduction of toxic SOD1 proteins has been proposed using antisense oligonucleotides (ASOs).25 ASOs are short, synthetic oligonucleotide sequences that bind to target mRNA in a sequence-specific manner through Watson–Crick base pairing; they are degraded by endogenous RNase.25,26 ASOs cannot cross the blood–brain barrier and must be infused intrathecally.27 Continuous intrathecal infusion of ASOs via osmotic pumps reduced SOD1 protein and mRNA levels throughout the brain and spinal cord and prolonged survival in both a rodent (SOD1 rat) and a primate (rhesus monkey) model.28 Initial human clinical trial results suggest that intrathecal infusion of ASOs via lumbar puncture is safe and tolerable.27

Similar strategies have been employed to target other toxic gain of function ALS genes. Sustained ASO-mediated lowering of C9orf72 RNA throughout the central nervous system of mice following an intrathecal (lateral ventricle) injection was found to be well tolerated.29 As it is currently unclear whether haploinsufficiency of C9orf72 is relevant to the disease process in ALS, it remains unclear if using ASOs to lower C9orf72 RNA is a viable treatment strategy. Currently, the only human ALS trial with ASOs is in SOD1, though this strategy might become an important and individually targeted approach, particularly as more ALS genes are discovered.

Cell-based treatments

In addition to pharmacological treatments, several clinical trials use stem cell transplantation, with two main therapeutic concepts behind this approach.30 These concepts include the potential replacement of motor neurons lost during the disease process and neural protection by improving metabolic support of the diseased motor neurons.

Neural stem cells

During development, pluripotent embryonic stem cells (ESCs) give rise to specific multipotent progenitor cell populations31 including neural stem cells (NSCs), which differentiate into neurons, astrocytes, and oligodendrocytes.32 Human NSCs can be derived from human ESCs33 or isolated from fetal neurologic tissue.34 When grafted into rat spinal cord, they retain their ability to differentiate into motor neurons, which integrate into spinal circuits.35

NSCs may be useful for ALS treatment. Human motor neuron administration delayed disease onset and prolonged survival in mouse36 and rat37 SOD1G93A ALS models. In a Phase I clinical trial, human NSCs (NSI-455RSC cells)38 were injected into the lumbar and/or cervical spinal cord without major adverse events or accelerated disease progression.39 A Phase II trial is in progress (NCT01730716).

Mesenchymal stem cells

Multipotent mesenchymal stem cells (MSCs) differentiate into osteoblasts, adipocytes, chondrocytes, and myocytes. They do not naturally differentiate into neural lineages but can be induced to do so.40 They can be isolated from bone marrow, cord, or peripheral blood and are thus more easily available than ESCs and, depending on the source, may not require immunosuppression.

MSCs may be useful for ALS treatment as a delivery vehicle to the central nervous system. Intraventricular injection of MSCs overexpressing glucagon-like peptide 1, an antioxidant with neuroprotective property, improved survival in the SOD1 mouse model.41 Injection of human MSCs overexpressing growth factors into the musculature of SOD1 rats reduced neuromuscular junction denervation and delayed disease progression.42 A synergistic effect was observed in overexpression of both vascular endothelial growth factor and glial cell line-derived neurotrophic factor.43 Injections of unmodified MSCs have also shown benefits on survival and disease progression in the SOD1 mouse model,44 possibly due to endogenous production of neuroprotective factors, which improves motor neuron metabolic support. Human autologous MSCs can be differentiated into neurotrophic factor secreting cells. A recent study showed that injection of these cells intrathecally and intramuscularly in an ALS patient treated on a compassionate basis was safe and clinically beneficial.45 A Phase I/II study in Israel was completed but no study results have been published (NCT01777646).

Several ALS clinical trials assessed the safety of MSC transplantations into the spinal cord46,47 or brain of ALS patients.48,49 These injections were safe without a clear clinical benefit. Postmortem pathological analysis of patients’ spinal cords showed more motor neurons and fewer degenerative ubiquitin deposits, suggesting neurotrophic activity in the grafted cells.49 Intrathecal MSC application has been shown to be safe via lumbar puncture50 as well as Ommaya reservoir.51

Another approach utilizing MSCs is subcutaneous injection of granulocyte colony-stimulating factor to mobilize endogenous MSCs, with52 or without53 collection and reinfusion of peripheral blood stem cells. Long-term administration of granulocyte colony-stimulating factor is safe54 and leads to persistent mobilization of hematopoietic stem cells55 but has no effect on the disease course.56

Olfactory ensheathing cells

Mammalian olfactory neurons regenerate throughout life from a stem cell layer at the base of the epithelium57 and are enfolded and guided by olfactory ensheathing cells (OECs) in the olfactory bulb.58

Based on findings in rodent spinal cord injury models59 and spinal cord injury clinical trials,60 OECs were applied for ALS treatment. Spinal grafts showed increased survival of SOD1 rats and slowing of motor neuron loss.61 Before there was clear evidence of benefit in an animal model, a laboratory in People’s Republic of China grafted OECs in ALS patients based on spinal cord injury clinical trials.62 OECs extracted from human fetal olfactory bulbs were injected into the bilateral corona radiata in 15 patients who were compared to 20 untreated controls. Over a 4-month follow-up period, a five-point difference in the ALS functioning rating scale–revised (ALSFRS-R) was detected. The study was halted as the authors felt there was “conclusive proof of positive and beneficial results”.63 Simultaneously, this group enrolled 327 patients in a noncontrolled trial that compared injection of OECs into the spinal cord, the bilateral corona radiata, or both. They reported improved ALS functioning rating scale and normalized electromyographical findings 4 weeks after transplantation, with no differences between the three groups.64 These results are largely contested and no further follow-ups were conducted. Despite this, hundreds of additional patients underwent OEC grafting in People’s Republic of China based on these results, some with multiple injections. The authors reported improved ALS functioning rating scale after each injection but diminished response after repeated injections.65 Independent follow-up studies on patients who received OEC transplants in People’s Republic of China could not confirm the reported observations.66 Postmortem studies did not suggest neuroprotection or axonal regeneration.67

Induced pluripotent stem cells

The discovery of induced pluripotent stem cells (iPSCs) showed that pluripotency can be induced in adult somatic mouse cells via introduction of transcription factors.68 Similarly, human iPSCs can be generated from human fibroblasts.69 iPSCs differ from human ESCs in gene expression and DNA methylation patterns but are germline-competent,70 generate all three germ layer cell types,71 and form active motor neurons.72 The potential for iPSC technology is enormous as it allows for a limitless supply of autologous pluripotent cells that can be reintroduced into the patient without immunosuppression. However, the current knowledge about these cells and ability for clinical application is limited.73

iPSCs have several important potential applications in ALS. Neural progenitor cells derived from human iPSCs survived and showed neuronal phenotypes when grafted into the spinal cord of SOD1 rats.74 Intrathecal or tail vein cell injection in SOD1 mice significantly improved survival and neurological function.75 Transplantation of glial-restricted precursor cells derived from human iPSCs targets astrocytic dysfunction observed in ALS and prolongs the lifespan of SOD1 mice.76

Besides possible clinical applications, it is important to emphasize the role that iPSCs play in modeling diseases in vitro. Several groups used either iPSCs derived from ALS patients77,78 or motor neurons derived from these iPSCs79,80 to further study ALS pathophysiology.

Symptomatic treatment

As the treatment options for ALS continue to be limited, symptomatic treatment is very important in the care of ALS patients. Specialized clinics provide multidisciplinary care by neurologists, specialty nurses, physical, occupational, respiratory, and speech therapists, dieticians, and social workers. The benefits of multidisciplinary clinics have been demonstrated in several studies, including survival8183 and quality of life84 when compared to patients seen in general neurology clinics. Both American85 and European guidelines86 recommend multidisciplinary care.


Dyspnea and respiratory compromise are common progressive symptoms, with several possible interventions. Respiratory muscle training is often recommended, but the evidence to support its benefit is limited.87 Noninvasive positive pressure ventilation (NIV) has been shown to not only improve quality of life88 but also prolong life, especially in patients without significant bulbar dysfunction and in those who are able to tolerate daily use of at least 4 hours.89,90 A potential additive to NIV is diaphragmatic pacing, especially in patients with bulbar symptoms, as the effectiveness of NIV correlates inversely with the severity of bulbar symptoms.91 In diaphragmatic pacing, electrodes are implanted in each hemidiaphragm, helping to provide maximal contraction of the diaphragm. In an open-label pilot study, 16 patients were implanted and showed benefits on survival (when compared to historical controls) and quality of life (as sleep dysfunction was reduced).92 Results of small follow-up studies have been mixed.93,94 Large, randomized controlled trials comparing NIV and diaphragmatic pacing are ongoing in the United States and Europe.95 Invasive ventilation remains another option to prolong survival.96 This is generally well tolerated97 but is rarely selected for a variety of reasons, including patient’s wishes and difficulties in home care.

Medications including opiates and benzodiazepines can be helpful in symptomatic treatment of dyspnea and dyspnea-related anxiety.98


About 25% of patients with motor neuron disease suffer from sialorrhea due to pseudohypersalivation.99 The majority of the treatments used for sialorrhea in ALS patients have not been studied in randomized controlled trials so there are no clear guidelines. Anticholinergic medications are generally recommended first.85 There are several oral agents, including atropine, glycopyrrolate, and amitriptyline. Transdermal application of hyoscyamine or scopolamine has the advantage of a constant concentration of drug in the circulation.100 For patients with sialorrhea refractory to medical therapy, salivatory gland botulinum toxin injections are an option, which lead to a significant decrease in saliva volume101 and have been shown to improve quality of life.102 Another alternative for treatment of refractory sialorrhea is radiation therapy of salivary glands.103

Respiratory secretions

Management of respiratory secretions and thick mucus can additionally become a major issue. Thick mucus production can be a symptom of ALS, medication side effect, or due to dehydration. Following insurance of good hydration and adjustment of medications, specific medication treatments can be added including mucolytics like N-acetylcysteine.85 Cough-assist and suction devices can be used to reduce the difficulty many patients experience with clearing respiratory secretions.104 Besides improving quality of life, these interventions have the potential to reduce hospitalizations.105


Dyspnea often coincides with dysarthria. Speech therapy along with assistive devices is recommended.85 Communication devices greatly improve the patients’ mood and quality of life.106

Dysphagia and weight loss

Nutrition management is another important goal in the treatment of ALS, as patients will develop dysphagia due to bulbar muscular weakness. In the early stages, this can be managed by modifying the consistency of food and fluids and teaching swallowing techniques. To ensure adequate nutrition and hydration as well as to stabilize weight loss, placement of a percutaneous endoscopic gastrostomy (PEG) tube is offered to many ALS patients with dysphagia.107 Nutritional status is an independent prognostic factor for survival in patients with ALS.108 However, there is inconclusive data whether placement of a PEG tube actually provides significantly improved nutrition, quality of life, or survival.109 For patient safety, a PEG tube should be placed before the patient’s vital capacity falls below 50% of predicted,85 even if no significant dysphagia is present at that time, as post-PEG deaths have been associated with reduced vital capacity.107

Muscular symptoms

Muscle issues including progressive weakness, cramps, and spasticity are cardinal features of ALS. Regular exercise of moderate intensity is generally recommended and has been found to improve quality of life, although the long-term benefit is unclear.110 Muscular cramps are a common complaint of ALS patients in all stages of the disease. Despite a number of medications undergoing trials so far, there has been no evidence supporting any specific intervention for muscle cramps in ALS.111 In practice, baclofen and gabapentin are frequently used to treat these. Baclofen is also often used to treat spasticity and is equally effective as tizanidine.112


Fatigue can be debilitating and is a common symptom of ALS. It is often associated with malnutrition or early respiratory failure. Fatigue is a potential medication side effect of many medications including riluzole,85 and medication adjustment should be considered. Multiple factors contribute to poor sleep which should be addressed throughout the disease course, and particularly with new complaints of fatigue. Depression should also be considered, as it is a common cause of fatigue and can benefit from treatment.113 Modafinil has been shown to have a positive effect on fatigue and sleepiness.114,115

Pseudobulbar affect

Pseudobulbar affect manifests as sudden episodes of uncontrollable laughter or crying without a provoking stimulus and is common in ALS. Dextromethorphan/quinidine has been shown to be effective in reducing the frequency and severity of emotional lability.116 The combination is necessary as dextromethorphan is rapidly metabolized if administered alone; quinidine reduces the metabolism via CYP2D6 inhibition. This combination has been approved by the FDA for pseudobulbar affect in ALS and represents the second FDA-approved drug specifically for ALS.


ALS remains a progressive motor neuron disease with a mean survival of 2–5 years. Symptom-based management of ALS in the setting of multidisciplinary clinics remains the most important current treatment strategy for the individual patient, as no curative therapies exist. Two decades after the first publication on using riluzole for treatment in ALS, this remains the only FDA-approved disease-modifying therapy. A large number of studied drugs showed promising results in animal models but failed translation to the human patient. One of the many difficulties in finding a treatment is the lack of understanding of pathophysiology of ALS. Yet, we remain optimistic about the medication treatments in developmental stages.

Novel therapeutic approaches with ASOs and stem cells have yet to show clear efficacy in humans; however, these remain exciting future directions of the field. Both have promising results in rodent and primate models of ALS. Early human trials have confirmed the safety of several of the potential methods. Preclinical studies showed the most convincing results in studies using NSCs. However, MSCs are more frequently used as they are more readily available and can easily be harvested and reintroduced into the patient without necessary immunosuppression.


The authors report no conflicts of interest in this work.



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