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Embarking On A Path To Hope

If you’ve heard of ALS before, it’s probably because in 2014 you poured a bucket of ice-cold water all over yourself for the ALS ice bucket challenge. But how much do you actually know about this devastating disease?

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that leads to the loss of motor neurons, causing paralysis and ultimately death within 2-5 years of diagnosis. Motor neurons connect the brain to the muscles, and send signals which cause muscles to contract and relax. When motor neurons die, the connection is lost, thereby causing paralysis. Mortalities are mainly a result of respiratory failure caused by paralysis of the muscles of the diaphragm.

In most patients, the cause of ALS is unknown. Approximately 10% of patients have a familial form of the disease and have a family history of ALS, due to a common genetic mutation. However, the majority of patients (~90%) have sporadic ALS.

Patients can also be categorized according to the site of symptom onset. Most patients experience limb onset, feeling weakness in an arm or leg, whereas other patients have bulbar onset, exhibiting weakness in muscles of the face, mouth and throat.

Over the last decade, sequencing of patients’ genomes has helped pinpoint which genetic mutations are most commonly correlated with ALS. The genes that are most associated with the development of ALS are TDP-43, SOD1, FUS and C9OFR72.

Although no common underlying cause of ALS has been found, there are many pathologies that have been shown to cause overall cell death and paralysis. One of the main accepted underlying mechanisms is extensive neuroinflammation, in which astrocytes and glial cells (the immune system of the brain) become toxic instead of neuroprotective. Furthermore, the dysregulation of RNA metabolism, causing under-or overexpression of RNA, leads to the production of ubiquitous, aberrant binding proteins, and accumulation of toxic RNA. Other pathologies include aggregation of misfolded proteins in the cytoplasm, as well as glutamate ecotoxicity, mitochondrial stress, endoplasmic reticulum dysfunction, and iron accumulation.

Due to the complexity of the disease, the diagnosis of ALS is usually slow, typically lasting about a year from symptom onset. To date, there is no test to diagnose ALS, and diagnosis is usually achieved by disputing other diseases until ALS is the only option left.

There is currently no cure, and the two available treatments have limited efficacy, giving patients only a few extra months of life.

There are estimated to be only half a million patients with ALS worldwide. About 20,000 live in the US, where 5,000 people are diagnosed each year. However, thanks to the aforementioned ice bucket challenge, there has been increased global recognition and funding for ALS research in recent years. ALS patients Pat Quinn and Pete Frates launched the ice bucket challenge, which successfully raised over $220 million. The money has been allocated to various areas of research and development, as well as patient support in the ALS field, and has become the legacy of Quinn and Frates, who have since succumbed to the disease.

With scientific research having vastly expanded our understanding of the pathologies that cause ALS, the ALS field is not the same as it was 20 years ago. Patients who are diagnosed today have hope in the way of more clinical trial options to participate in. Therefore, despite the severity and complexity of the disease, there is a light at the end of the tunnel.

 

This is the first of five articles in our series for ALS Awareness Month (May 2021), in order to provide insights into the disease and the complexity of drug development.

Click here for the next article of the series

 

 

 

- Avital Pushett

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