ALS: Drug Therapy From the Bench to the Bedside
Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular atrophy and weakness resulting from loss of both upper and lower motor neurons. It was first clinically and pathologically described by Charcot in 1874. Amyotrophic lateral sclerosis gained notoriety after the New York Yankee baseball player, Lou Gehrig, was diagnosed in 1939; to this day, it is commonly referred to as "Lou Gehrig's disease" in the United States. The disease generally progresses rapidly and is inevitably fatal. The cause of death is relatively uniform—typically due to respiratory failure. The incidence ranges from 1.5 to 2.5 per 100,000 per year, with a lifetime risk of ~1:400. The mean age of onset is ~60 years, with a male predominance of 1.3:1. The median survival is 2 to 4 years from symptom onset, although a small percentage live longer than 10 years. The differential diagnosis is small and misdiagnosis is estimated to be less than 10%.
Familial ALS is clinically indistinguishable from sporadic ALS. Familial ALS is generally defined as the history or presence of ALS in one or more 1- or 2-degree family members of a person with ALS. The rate of familial ALS is 5 to 10%. In 1993, a superoxide dismutase (SOD1) mutation was discovered that can lead to ALS. Despite this advance, it was nearly a decade before the next gene mutation was discovered. There has recently been a rapid expansion in the number of recognized ALS mutations, with 10 different ALS mutations identified. It is estimated that the most common ALS genes, SOD1, TDP-43, and FUS mutations and the C9orf72 hexanucleotide repeat, account for 65% of familial ALS cases in the United States, although the percentage of ALS linked to these genes varies based on geographical region. For some of the genes, ALS is not the only neurodegenerative phenotype expressed. For example, the C9orf72 hexanucleotide repeat, is also a common cause of frontotemporal dementia (FTD), sometimes in combination with ALS, and sometimes in isolation with either ALS or FTD.
There are currently >50 actively enrolling clinical trials for ALS listed on clinicaltrials.gov, with several times that number completed. Most drugs for ALS come through a traditional route of identifying a target and then screening for compounds that modify the activity of the target, then optimizing hits within the identified drug family to help select the ideal compound. However, drugs are increasingly coming from large screening efforts that examine compounds without known targets. This helps to identify potential drug treatments with mechanisms already known or thought to be related to ALS, but also identify potential drug treatments that cause reconsideration of the disease pathway. One of the first nontraditional screens for ALS and other selected neurologic diseases was the large community screening effort by the National Institute of Neurological Disorders and Stroke (NINDS) in the early 2000s. About 1,000 compounds were screened in a variety of biologic assays, the majority of which were already in use for nonneurologic diseases, and several had positive results. Here we will review proposed ALS disease mechanisms followed by historical and upcoming drug studies.
Abstract and Introduction
Abstract
Amyotrophic lateral sclerosis (ALS) is an unrelenting progressive neurodegenerative disease causing progressive weakness, ultimately leading to death. Despite aggressive research, the pathways leading to neuronal death are incompletely understood. Riluzole is the only drug clinically proven to enhance survival of ALS patients, but its mechanism of action is not clearly understood. In this article, the proposed pathophysiology of ALS is reviewed including glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, autoimmune mechanisms, protein aggregation, SOD1 accumulation, and neuronal death. Based on these mechanisms, past major ALS drug studies will be reviewed as well as promising current ALS drug studies, focusing on the advancement of these studies from the bench to the patient's bedside.
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscular atrophy and weakness resulting from loss of both upper and lower motor neurons. It was first clinically and pathologically described by Charcot in 1874. Amyotrophic lateral sclerosis gained notoriety after the New York Yankee baseball player, Lou Gehrig, was diagnosed in 1939; to this day, it is commonly referred to as "Lou Gehrig's disease" in the United States. The disease generally progresses rapidly and is inevitably fatal. The cause of death is relatively uniform—typically due to respiratory failure. The incidence ranges from 1.5 to 2.5 per 100,000 per year, with a lifetime risk of ~1:400. The mean age of onset is ~60 years, with a male predominance of 1.3:1. The median survival is 2 to 4 years from symptom onset, although a small percentage live longer than 10 years. The differential diagnosis is small and misdiagnosis is estimated to be less than 10%.
Familial ALS is clinically indistinguishable from sporadic ALS. Familial ALS is generally defined as the history or presence of ALS in one or more 1- or 2-degree family members of a person with ALS. The rate of familial ALS is 5 to 10%. In 1993, a superoxide dismutase (SOD1) mutation was discovered that can lead to ALS. Despite this advance, it was nearly a decade before the next gene mutation was discovered. There has recently been a rapid expansion in the number of recognized ALS mutations, with 10 different ALS mutations identified. It is estimated that the most common ALS genes, SOD1, TDP-43, and FUS mutations and the C9orf72 hexanucleotide repeat, account for 65% of familial ALS cases in the United States, although the percentage of ALS linked to these genes varies based on geographical region. For some of the genes, ALS is not the only neurodegenerative phenotype expressed. For example, the C9orf72 hexanucleotide repeat, is also a common cause of frontotemporal dementia (FTD), sometimes in combination with ALS, and sometimes in isolation with either ALS or FTD.
There are currently >50 actively enrolling clinical trials for ALS listed on clinicaltrials.gov, with several times that number completed. Most drugs for ALS come through a traditional route of identifying a target and then screening for compounds that modify the activity of the target, then optimizing hits within the identified drug family to help select the ideal compound. However, drugs are increasingly coming from large screening efforts that examine compounds without known targets. This helps to identify potential drug treatments with mechanisms already known or thought to be related to ALS, but also identify potential drug treatments that cause reconsideration of the disease pathway. One of the first nontraditional screens for ALS and other selected neurologic diseases was the large community screening effort by the National Institute of Neurological Disorders and Stroke (NINDS) in the early 2000s. About 1,000 compounds were screened in a variety of biologic assays, the majority of which were already in use for nonneurologic diseases, and several had positive results. Here we will review proposed ALS disease mechanisms followed by historical and upcoming drug studies.
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