New therapeutic targets for amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological disorders, affecting approximately half a million people worldwide. Currently there is no cure or prevention for ALS. Although ALS is a rare condition, it places a tremendous socioeconomic burden on patients, family members, caregivers and health systems.

Areas covered: The review examines the mechanisms that may contribute to motor neuron degeneration in ALS, among which oxidative damage, glutatamate excitoxicity, mitochondrial dysfunction, impaired axonal transport, apoptotic cell death, growth factor deficiency, glial cell pathology and abnormal RNA metabolism are potential targets for ALS treatment. The article provides an overview of clinical trials performed to date in attempts to treat ALS with regard to molecular mechanisms and pathways they act on. It also discusses new trials based on recently developed molecular biology techniques.

Expert opinion: Despite significant effectiveness of several potential therapeutics observed in preclinical trials, the results were not translatable to patients with ALS. The development of effective treatments of ALS strictly depends on understanding the primary cause of the disease. This goal will only be achieved when we identify the trigger point for motor neuron death in ALS.     

New therapeutic targets for amyotrophic lateral sclerosis

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological disorders, affecting approximately half a million people worldwide. Currently there is no cure or prevention for ALS. Although ALS is a rare condition, it places a tremendous socioeconomic burden on patients, family members, caregivers and health systems. AREAS COVERED: The review examines the mechanisms that may contribute to motor neuron degeneration in ALS, among which oxidative damage, glutatamate excitoxicity, mitochondrial dysfunction, impaired axonal transport, apoptotic cell death, growth factor deficiency, glial cell pathology and abnormal RNA metabolism are potential targets for ALS treatment. The article provides an overview of clinical trials performed to date in attempts to treat ALS with regard to molecular mechanisms and pathways they act on. It also discusses new trials based on recently developed molecular biology techniques. EXPERT OPINION: Despite significant effectiveness of several potential therapeutics observed in preclinical trials, the results were not translatable to patients with ALS. The development of effective treatments of ALS strictly depends on understanding the primary cause of the disease. This goal will only be achieved when we identify the trigger point for motor neuron death in ALS.     

Humanin and colivelin: neuronal-death-suppressing peptides for Alzheimer's disease and amyotrophic lateral sclerosis

Humanin (HN), a 24-amino-acid neuroprotective peptide, was originally found in the occipital lobe of an autopsied Alzheimer's disease (AD) patient. HN inhibits neuronal death by binding to its specific receptor on the cell membrane and triggering a Jak2/STAT3 prosurvival pathway. The activation of this pathway may represent a therapeutic approach to AD. HN also exhibits neuroprotective activity against toxicity by familial amyotrophic lateral sclerosis (ALS)-related mutant superoxide dismutase (SOD1). Recent investigations established that AGA-(C8R)-HNG17, a 17-amno-acid derivative of HN, is 10(5) times more potent as a neuroprotective than HN; at 10-picomolar and higher concentrations in vitro it completely suppresses neuronal death. Moreover, a 26-amino-acid peptide colivelin (CL), composed of activity-dependent neurotrophic factor (ADNF) C-terminally fused to AGA-(C8R)-HNG17, provides complete neuroprotection at 100-femtomolar or higher concentrations in vitro. A series of experiments using mouse AD and ALS models further established the efficacy of HN derivatives, including CL, against these diseases in vivo. HN and CL can be viewed as drug candidates for neuronal death suppression therapy in AD or ALS.     

Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis

Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable alpha-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.     

Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disease that destroys both upper and lower motor neurons, resulting in spasticity, diffuse muscular atrophy, weakness, and ultimately death from respiratory failure. It is presumed that in the vast majority of cases, ALS is acquired and occurs sporadically, although the exact etiology is unknown. Recent, emerging evidence suggests that neuro-inflammation may be a pathological characteristic of this disease; this could represent a potential therapeutic target for a pharmacological agent to help treat this severe disease. This article reviews the current research in this area and discusses theoretical and clinical ramifications of these recent findings.     

Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis

Two forms of amyotrophic lateral sclerosis (ALS) are known, the familial (FALS), due in part to mutations in superoxide dismutase 1 (SOD1), and the sporadic (SALS), which accounts for > 90% of all cases. The cause of SALS is not known, but excitotoxicity due to overactivation of glutamate receptors may mediate the motor neuron degeneration in the spinal cord, which is the hallmark of this disease. Overactivation of calcium-permeable α-amino-3-hydroxy-5-isoxazole propionate receptors lacking the subunit glutamate receptor 2, leading to an increase in calcium cytoplasmic concentration, seems to play an important role in the mechanism of neuronal death. The knowledge of this mechanism, in addition to other factors, provides several possible targets for therapeutic strategies that are reviewed in this article. Some of these strategies have proven to be partially effective in both human mutant superoxide dismutase 1 transgenic rodents (FALS model) and the few existing in vivo models of spinal motor neurodegeneration induced by excitotoxicity (SALS models), although observable benefits are still to be shown in clinical trials.     

Therapeutic developments in the treatment of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurons. The mechanisms and processes responsible for the selective loss of motor neurons are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by ～ 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease.     

Therapeutic developments in the treatment of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease characterised by the selective death of motor neurones. The mechanisms and processes responsible for the selective loss of motor neurones are still unknown, however several hypotheses have been put forward, including oxidative damage and/or toxicity from intracellular aggregates due to mutant superoxide dismutase-1 activity, axonal strangulation from cytoskeletal abnormalities, loss of trophic factor support and glutamate-mediated excitotoxicity. These theories are based on a better understanding of the genetics of amyotrophic lateral sclerosis and on biochemical and pathological analysis of post-mortem tissue. They have led to the development of appropriate animal and cell culture models, allowing the sequence of events in motor neuronal degeneration to be unravelled and potential therapeutic agents to be screened. Unfortunately, the majority of therapeutics found to be efficacious in the animal and cell culture models have failed in human trials. Riluzole is still the only proven therapy in humans, shown to extend survival of amyotrophic lateral sclerosis patients by approximately 3 months, but it has no effect on muscle strength. Other potential therapeutic approaches are being identified, including inhibition of caspase-mediated cell death, maintenance of mitochondrial integrity and energy production, regulation of glutamate homeostasis, reduction of inflammation and control of neurofilament synthesis. Hopefully, in the near future some new agents will be found that can alter the course of this devastating and fatal disease.     

Drugs in clinical development for the treatment of amyotrophic lateral sclerosis

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future.

Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs.

Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient’s associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.     

Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis

ABSTRACT

Introduction

To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy.     

Clinical utility of neuroprotective agents in neurodegenerative diseases: current status of drug development for Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis

Introduction: According to the definition of the Committee to Identify Neuroprotective Agents in Parkinson's Disease (CINAPS), "neuroprotection would be any intervention that favourably influences the disease process or underlying pathogenesis to produce enduring benefits for patients" [Meissner W, et al. Trends Pharmacol Sci 2004;25:249-253]. Preferably, neuroprotective agents should be used before or eventually during the prodromal phase of the diseases that could start decades before the appearance of symptoms. Although several symptomatic drugs are available, a disease-modifying agent is still elusive. Areas covered: The aim of the present review is to give an overview of neuroprotective agents being currently investigated for the treatment of AD, PD, HD and ALS in clinical phases. Expert opinion: Development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages, both conceptual and methodological. Novel solutions might be offered by evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multi-target approaches and network pharmacology.     

Management of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor neurons, in both the spinal cord and medulla (lower motor neurons) and cerebral cortex (upper motor neurons). Even though ALS remains fatal, several advances have been made during the last decade in improving the consequences of motor dysfunction, quality of life and survival time of patients. Treatment of ALS cannot be restricted to riluzole, the only molecule that has been proved to modify the evolution of the disease. Symptomatic treatments have an important role in controlling the major consequences of the disease, such as pain, sleep disorders, spasticity, hypersialhorroea, emotional lability, depression and digestive disorders (constipation and reflux). All these symptoms need to be recognized and their possible causes identified in order to provide the most appropriate management of patients with ALS. However, an advance in the daily care of patients is the identification of two important phenomena that occur during the evolution of the disease: swallowing difficulties and the occurrence of diaphragmatic dysfunction. For both, specific medical interventions have been developed to allow correction of the consequences (i.e. weight loss and respiratory insufficiency). Although no controlled trials have been performed, observational studies suggest that gastrostomy and non-invasive ventilation may improve at least quality of life and survival. All of these various approaches, pharmaceutical and non-pharmaceutical therapies, are prescribed according to individual symptoms and require the involvement of a large range of health professionals. This multidisciplinary approach in ALS clinics is considered to be one of the more important factors impacting on survival rate and appears to be the gold standard of medical care of ALS patients. Important findings have been made in understanding the nature of the degenerative process that affects the motor neurons. All these data have allowed new therapeutic molecules to be tested alone or in combination with riluzole. Despite the negative results obtained until now, we hope to demonstrate very soon a greater improvement in therapy.     

Treatment of amyotrophic lateral sclerosis

Survival of patients with amyotrophic lateral sclerosis (ALS) is improving. Timely and more frequent implementation of bimodal passive airway pressure (BIPAP) and percutaneous endoscopically placed gastrostomy (PEG) may be the major factors impacting on longer survival. However, several drugs recently subjected to rigorous clinical trials have demonstrated significant results or encouraging trends. ALS is a complex disease in which aging neurons are subjected to a variety of susceptibility genes, most of which remain to be discovered, that interact with equally unrecognised environmental factors. This makes it unlikely that a single therapeutic agent will be of value. The thrust must be on polypharmacy. The 'cocktail' that will eventually be of greatest benefit has yet to be formulated. It might contain glutamate N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists, antioxidants or a combination of trophic factors and neuroprotective agents. This statement is made with the understanding that the aetiopathogenesis of ALS is far from clear. Drug delivery is a problem and better delivery systems are needed. The efficacy of some of the medications that presently only induce modest benefit may be improved by liposomal packaging, use of a patch or inhalation delivery or intraventricular pump reservoirs. There is a great need to develop an early marker of ALS and sensitive reproducible measures of disease progression. This will curtail the present need for large, lengthy and very expensive clinical trials. The new millennium will see the advent of targeted therapy using viral vectors which can deliver replacement genes, trophic factors and other drugs to degenerating neurons; transplantation of neural progenitor cells which can become mature functioning neurons; anti-apoptotic agents which will allow neurons to survive longer; and mechanisms that can protect the telomerase maintenance system which is so crucial in the immortalisation of cells.     

Galectin-1 as a potential therapeutic agent for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects almost selectively motor neurons in the central nervous system. Most ALS patients die within five years of onset. One of the neuropathological features of ALS is an "axonal spheroid," a large swelling of a motor axon within the anterior horn of the spinal cord; this abnormal structure seems to be related to the pathogenesis of motor neuron degeneration in ALS. In 2001, using biochemical and immunohistochemical methods, we found an accumulation of galectin-1 in ALS spheroids. By immuno-electron microscopy, the galectin-1 accumulated in the spheroids was observed to be closely associated with neurofilaments. Furthermore, we observed a marked depletion of galectin-1 in the skin of ALS patients; another abnormality frequently observed in ALS. These findings, therefore, suggest that galectin-1 may be involved in the pathogenesis of ALS. It is known that an oxidized form of galectin-1 promotes axonal regeneration; however, it is not known whether oxidized galectin-1 has a beneficial or an adverse effect on the pathophysiology of ALS. To examine this issue, we administered oxidized galectin-1 to transgenic mice with H46R mutant SOD1, an ALS model mouse. The results showed that the administration of oxidized galectin-1 improved the motor activity, delayed the onset of symptoms, and prolonged the survival of the galectin-1-treated mice. Furthermore, the number of remaining motor neurons in the spinal cord was more preserved in the galectin-1-treated mice than in the non-treated mice. We conclude that galectin-1 could be a candidate agent for the treatment of ALS.     

Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, neurodegenerative disease. Although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role. Edaravone works in the central nervous system as a potent scavenger of oxygen radicals. In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebrospinal fluid.

Areas covered: Three clinical trials, one phase II open-label trial, and two phase III placebo-control randomized trials were reviewed. In all trials, the primary outcome measure was the changes in scores on the revised ALS functional rating scale (ALSFRS-R) to evaluate motor function of patients.

Expert opinion: The phase II open label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the cerebrospinal fluid. One of the two randomized controlled trials showed beneficial effects in ALSFRS-R, although the differences were not significant. The last trial demonstrated that edaravone provided significant efficacy in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted. Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity. Therefore, combination therapy with edaravone and riluzole should be considered earlier.     

Therapeutic developments in amyotrophic lateral sclerosis

There is currently no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating disorder of the human nervous system that, due to motoneurone degeneration, causes progressive loss of muscle function and death. The relentless progression of ALS and the uniformly poor prognosis have been unhindered by a variety of therapeutic agents tested in previous clinical studies. Recently, two drugs, namely riluzole and recombinant human insulin-like growth factor-I (IGF-1), have been reported to benefit patients with ALS by improving survival or slowing disease progression. Several other drugs, such as gabapentin and various neurotrophic factors, are being investigated in on-going clinical trials. Therapeutic developments in ALS have been hampered by the fact that the precise cause of the disease remains unknown. In addition, there are considerable variations in disease related characteristics among patients, rendering accurate measurements of disease progression difficult. Advances in theories of pathogenesis, such as genetic factors, glutamate excitotoxicity, oxidative stress, autoimmune mechanism and cytoskeletal abnormality will help guide the development of future therapies. Newer approaches to therapy may include suitable glutamate antagonists, small molecules that augment neurotrophic factor function, and anti-oxidants. Combination therapy of effective agents should be considered.     

Cost-benefit analysis of riluzole for the treatment of amyotrophic lateral sclerosis

We conducted a cost-benefit analysis of riluzole therapy in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease; Lou Gehrig's disease). The survival of patients with ALS increased by around 3 months as a result of riluzole therapy, from 3 to 3.25 years. A 3-month delay in hospitalisation was also expected as a result of riluzole therapy, resulting in a saving of $US40 per patient (1996 values). This gain was opposed by the additional costs per patient of bi-monthly serum ALT monitoring ($US234), 2 days of extra day-hospital observation ($US369) and other medical costs ($US79), as well as extra outpatient visits ($US26) and costs of medication other than riluzole ($US90), resulting from increased longevity. Using riluzole (at a cost of $US2247 per patient) resulted in an extra burden of $US757 on health services for the gain of an extra 3 months of life expectancy. Thus, health-service costs per life-year gained were $US12,013. Despite the increase in health-service costs as a result of increased longevity, the overall resource benefits to society from using riluzole amounted to $US2884 due to increased productivity benefits, giving a benefit: cost ratio of 1.28:1. Total benefits to society, including a valuation of 3 extra months of life ($US3599), amounted to $US6483, giving a benefit: cost ratio of 2.89:1. Therefore, from a societal perspective, the potential benefits of riluzole in patients with ALS clearly exceed costs.     

Therapeutic developments in amyotrophic lateral sclerosis

There is currently no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating disorder of the human nervous system that, due to motoneurone degeneration, causes progressive loss of muscle function and death. The relentless progression of ALS and the uniformly poor prognosis have been unhindered by a variety of therapeutic agents tested in previous clinical studies. Recently, two drugs, namely riluzole and recombinant human insulin-like growth factor-I (IGF-1), have been reported to benefit patients with ALS by improving survival or slowing disease progression. Several other drugs, such as gabapentin and various neurotrophic factors, are being investigated in on-going clinical trials. Therapeutic developments in ALS have been hampered by the fact that the precise cause of the disease remains unknown. In addition, there are considerable variations in disease related characteristics among patients, rendering accurate measurements of disease progression difficult. Advances in theories of pathogenesis, such as genetic factors, glutamate excitotoxicity, oxidative stress, autoimmune mechanism and cytoskeletal abnormality will help guide the development of future therapies. Newer approaches to therapy may include suitable glutamate antagonists, small molecules that augment neurotrophic factor function, and anti-oxidants. Combination therapy of effective agents should be considered.