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Mechanisms of ALS Medications

Jill Goslinga

In January 2024, Jill Ann Goslinga, MD, MPH, Assistant Professor, UCSF Department of Neurology, gave a special presentation about the mechanisms of ALS medications at the ALS Network’s (formerly the ALS Association Golden West Chapter) ASK ME educational webinar, “ALS Research and Care in 2024.” 

Dr. Goslinga provided an overview of the processes that cause cell injury, also known as ALS pathogenesis, and the connections to ALS medications including Tofersen (Qalsody), Edaravone (Radicava), Healey ALS Platform Regimens F and G, AMX0035 (Relyvrio), and Riluzole. Here are some highlights and excerpts from that presentation:

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The first ALS mechanism, or cause of motor neuron cell injury and death, is a problem with protein balance. 

  • Proteins need to be at the right place at the right time, and if they are not, this affects the motor neurons. In both sporadic and familial ALS, these proteins clump together, which is called abnormal protein aggregation.
  • These aggregates occur in the cytoplasm (responsible for holding the parts of the cell together and protecting them from damage) outside the cell’s nucleus. The abnormal clusters of these proteins impair the functions of nerve cells and eventually die, causing muscle weakness for people with ALS.
  • Additionally, there are issues with cell degradation; the process of proteins being broken down abnormally. In this process, lysosomes are the main recycling centers in the cell, and evidence from research is starting to show that lysosomal dysfunction is a potential treatment target for ALS and other neurodegenerative diseases.

Another mechanism of ALS is renegade RNA cells. 

  • This altered RNA function is often seen in the C9ORF72 mutation of ALS, and is a big contributor to the death of cells. In C9ORF72, long and unusual RNA sequences are made, and do not follow normal protein-building instructions.
  • Toxic aggregates are a result, which disrupt normal functions and cause cells to die off.

Another motor neuron damaging factor is the broken infrastructure of the cytoskeleton . 

  • The cytoskeleton is the infrastructure that helps maintain the shape and internal organization of the cell’s cytoplasm and helps move the motor neuron cell.
  • When the structure is affected, the transportation of the motor neuron is disrupted.

It is important to note that free radical damage (oxidative stress) and other damage that leads to molecular stress responses, harming motor neuron cells in the process. 

  • Oxygen is needed for cells to break down energy, and free radicals are one of the byproducts. Normally, toxic free radicals are cleaned up by proteins, one of them being superoxide dismutase.
  • SOD1 ALS mutations affect the process of cleaning up toxic free radicals, which cause abnormal protein aggregates.
  • Tofersen (Qalsody), is an ALS treatment that is injected into the spinal region to help treat people with the SOD1 mutation.
  • In addition, Edaravone (Radicava), is known for reducing the effects of free radicals. 

Currently, the Healey Platform Trial is testing two drugs, Regimen F (ABBV-CLS-7262) and Regimen G (DNL343).

  • Regimen F and Regimen G target integrated stress responses (ISR).
  • ISR acts as a “fire alarm” that helps healthy cells stop protein production.
  • In ALS, this “fire alarm” continues nonstop and causes stress granules that impair nerve function.

Finally, it is important to note the risks of “power outages” in ALS, or mitochondrial dysfunction. 

  • Mitochondria are the “power plants” of the cell that create the energy needed for cells to function. 
  • The dysfunction of the mitochondria can lead to progressive cell injury, leading to weakness of the muscles. 
  • AMX0035 (Relyvrio) may reduce this stress on the mitochondria and the endoplasmic reticulum that works closely with the mitochondria and cells.

The first FDA-approved ALS medication, Riluzole, works to reduce glutamate levels. 

  • Glutamate acts as “words” for nerve cells (neurotransmitters) to communicate with each other. 
  • In ALS, glutamate levels are high and become excessive “noise” that over-stimulates and puts stress on nerve cells. 

The presentation concluded with a discussion about a final potential mechanism contributing to ALS: neuroinflammation. 

  • Inflammation helps the body respond to damage or infection and is normal. 
  • It can be counterproductive and damage cells (abnormal neuroinflammation) including “support cells” around neurons such as astrocytes and microglia. 
  • This abnormal inflammation is a part of motor neuron death in ALS, and likely a part of a response rather than the main cause of cell death.

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The ALS Network is grateful to Dr. Goslinga for her time in creating this presentation for our ALS community. She is a recipient of the American Academy of Neurology’s Clinical Research Training Scholarship (CRTS) and the UCSF Dean’s Scholar Program in Population Health and Health Equity (PHHE). Her research includes clinical trials for ALS, as well as population-based health equity research into the impact of air pollution on ALS disease progression, and strategies to reduce geographic health inequities in access to multidisciplinary ALS care. 

You can watch the full presentation below:

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