Therapeutic Approaches to Treating ALS

In medicine, there are a few broad philosophical approaches to treating conditions. First, there’s prophylactic treatment; these are treatments that we can take to prevent the development of a condition, though these do not exist for all treatments. Some behaviors — these are called “risk factors” — can make it more likely that we will develop a condition, such as cigarette smoking and lung cancer. Though it’s not technically a “treatment,” if we currently engage in risky behavior and choose to cease that behavior, we are then reducing our likelihood of developing that condition. This is prophylactic in a different manner, but still, we are lowering those chances. Both of these approaches are less in the field of “treating,” and more in the realm of “preventing” disease, but they are relevant regardless. Once a condition develops and if the cause is unknown, all clinicians can really do is treat the progression of the disease and its symptoms. This is still a reactionary approach; these treatments are not fixing the root cause, so while the patient’s quality of life might improve upon symptom resolution, the condition (depending on what it is of course) likely remains. If the condition’s cause is known, then, treatment becomes a lot more promising as researchers are likelier to understand how therapeutics can help improve the state of the condition.

But treating conditions is only as simple as the condition. For complex conditions like Alzheimer’s, epilepsy, Parkinson’s, amyotrophic lateral sclerosis, and many others that affect the brain or the nervous system, treatment is quite difficult. Most treatments for these conditions seek to improve the symptoms and progression of the condition, but few treatments exist for most neurological conditions that have been shown to improve the underlying etiology.

This can be disheartening for patients, their loved ones, and the researchers and clinicians who work with those with ALS since it can feel like there is no end in sight. With ALS, which has proven to be a difficult puzzle in discerning strong evidence for a single cause; more likely, it will be found that ALS is a complex condition that arises from several different causes. It should be noted that how conditions are described — from cause to diagnosis to treatment — is rarely ever simple. Sometimes it can be, such as when a condition obeys basic Mendelian inheritance, such as cystic fibrosis or sickle cell anemia, are discovered. These conditions are single-gene diseases, meaning that when a single gene is disrupted or dysfunctional, patients present to the clinic with a many of the same common symptoms. The clinical presentation might be described first and treating that condition might still be complex, but the cause is usually pretty well-understood.

For complex conditions, which are usually caused by genetic, environmental, and behavioral factors, the cause of the condition in the broader population might never be fully understood. However, as researchers gain a better understanding into how much each factor plays into causing a given condition, it might be possible to understand what caused it in an individual. These are different ideas and how much they differ is an important distinction. There are between 12,000 and 15,000 Americans with ALS; since ALS is so heterogeneous, both in etiology and presentation, researchers might not be able to say what the exact contribution of each factor is for that entire population. What they might be able to do eventually, though, is describe what was the likely cause for many individuals based on their genetics, environment, and lifestyles.

Since ALS is so heterogeneous, there are multiple therapeutic approaches that are being investigated. First, a quick refresher if you haven’t read my previous blog on ALS (which overviewed a study that revealed multiple subphenotypes of ALS). ALS is a neurological condition that results in dysfunctional motion neuron function. There is no consensus on etiology and the condition is difficult to treat and monitor. As of now, ALS remains tragically fatal.

While the current state of ALS therapeutics is lacking, there remain several different approaches that have been proposed and are being investigated. These approaches fit within three different classifications: Pharmacological, gene, and stem cell therapy.

Pharmacological approaches are drug-based therapies. These therapies seek to improve altered mechanisms in ALS, which are believed to cause ALS or its symptoms. Currently there exists only two compounds that are FDA-approved to treat ALS: Edaravone (which goes by the drug name Radicava®), which aims to reduce oxidative stress, and riluzole, which inhibits glutamate release. Both of these compounds, which show only modest improvement in quality of life for patients, seek to improve ALS clinical outcomes by responding to what those aforementioned “altered mechanisms” that researchers have found to be more common in ALS patients than in people without ALS. This idea gets to the root of pharmacological approaches; these approaches seek to restore the altered mechanisms in these patients, but unfortunately, due to the immense complexity in the etiology of ALS and the nervous system, simply partially restoring one or a couple altered mechanisms does not resolve the full scope of the ALS cause in patients.

Alternatively, gene therapy has been proposed to help with ALS, although this approach relies on the understanding of the genetic factors that cause the condition in a given individual. Gene therapy at its most simple is modifying, deleting, or inserting the dysfunctional gene in an individual. Gene therapy does not only theoretically work for inherited conditions, but also those that are acquired, so long as the genetic component is understood. For some ALS patients, particularly those of whom with SOD1 or C9orf72 genes, gene therapy appears to be a promising option. It should be noted that the mechanism by which mutations in the SOD1 gene result in ALS are not clearly understood. The authors of one paper about ALS pathogenesis and therapeutic approaches emphasized this point about gene therapy for ALS: “This approach could only be used for a familial [inherited] form of ALS and not for [sporadic ALS] which represents the majority [90-95%] of cases.” Though a handful of gene therapies have been approved in the US, significant barriers remain before gene therapy can become a common and effective therapeutic strategy for most conditions. Gene therapy would be critical for those patients, but alternative approaches must be devised.

The last approach, and perhaps the most promising for ALS and other conditions, is stem cell therapy. Stem cells are the cells that haven’t developed into specialized cells yet, which is a process called cellular differentiation. Stem cells, then, as a medical approach, are differentiated into the specialized cells that can be used to repair damaged tissues in the body. For a condition such as ALS, stem cells could theoretically be used to repair the damaged motor neurons and neural protection. Stem cells can also provide insight into disease mechanisms; some researchers are developing stem cells to emulate the cells of people with certain conditions so they can understand disease mechanisms and how those cells will respond to drugs.

While pharmacological, gene, and stem cell therapies are the most prominent, they aren’t technically the only ones. In our bodies all the time, cells must communicate with one another. There are a variety of ways they communicate, including vesicles called exosomes and microvesicles, which pose as novel yet innovative potential therapeutics. These vesicles are secreted by cells, carry biological material, travel long distances, and act as conduits for communication between cells, all of which make them compelling vectors for reparative and protective processes.

Amyotrophic lateral sclerosis is a complex condition in its etiology, population demographics, and heterogeneous clinical presentation. These issues dovetail in such a way that the current landscape for ALS therapeutics is upside-down: Many opportunities, little-to-no available highly-effective therapies. With the amount of promising research and opportunity in all the fields — pharmacological, stem cell, gene, and even extracellular vesicles — the future appears to be quite bright.

Resources

1. Definition of risk factor – NCI Dictionary of Cancer Terms. (2011, February 2). [NciAppModulePage]. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/risk-factor
2. Gregor Mendel and Single-Gene Disorders | Learn Science at Scitable. (n.d.). Retrieved June 12, 2022, from http://www.nature.com/scitable/topicpage/mendelian-genetics-patterns-of-inheritance-and-single-966
3. Complex Diseases: Research and Applications | Learn Science at Scitable. (n.d.). Retrieved June 12, 2022, from http://www.nature.com/scitable/topicpage/complex-diseases-research-and-applications-748
4. Amyotrophic lateral sclerosis. (2019, January 31). https://www.cdc.gov/als/WhatisALS.html
5. Resting-state EEG reveals four subphenotypes of amyotrophic lateral sclerosis | Neuline. (n.d.). Retrieved June 12, 2022, from https://neulinehealth.com/resting-state-eeg-reveals-four-subphenotypes-of-amyotrophic-lateral-sclerosis/
6. Bonafede, R., & Mariotti, R. (2017). ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles. Frontiers in Cellular Neuroscience, 11, 80. https://doi.org/10.3389/fncel.2017.00080
7. FDA-Approved Drugs for Treating ALS. (n.d.). Retrieved June 12, 2022, from https://www.als.org/navigating-als/living-with-als/fda-approved-drugs
8. Frequently Asked Questions About Radicava – The ALS Association. (n.d.). Retrieved June 12, 2022, from https://secure2.convio.net/alsa/site/SPageNavigator/alsa_radicava_faq.html;jsessionid=00000000.app275b?NONCE_TOKEN=24EFC0450A473C68FF9DA9B591120D39
9. Gene Therapy. (n.d.). Retrieved June 12, 2022, from https://www.genome.gov/genetics-glossary/Gene-Therapy
10. Cappella, M., Ciotti, C., Cohen-Tannoudji, M., & Biferi, M. G. (2019). Gene Therapy for ALS—A Perspective. International Journal of Molecular Sciences, 20(18), 4388. https://doi.org/10.3390/ijms20184388
11. Berdyński, M., Miszta, P., Safranow, K., Andersen, P. M., Morita, M., Filipek, S., Żekanowski, C., & Kuźma-Kozakiewicz, M. (2022). SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity | Scientific Reports. Scientific Reports, 12(1), 103. https://doi.org/10.1038/s41598-021-03891-8
12. Cell Differentiation, Tissue | Learn Science at Scitable. (n.d.). Retrieved June 12, 2022, from https://www.nature.com/scitable/topicpage/cell-differentiation-and-tissue-14046412/
13. Pluripotent Stem Cells, iPs cells | Learn Science at Scitable. (n.d.). Retrieved June 12, 2022, from https://www.nature.com/scitable/topicpage/turning-somatic-cells-into-pluripotent-stem-cells-14431451/