Genetic Variants Linked To ALS Could Lead to New Treatments

For decades, amyotrophic lateral sclerosis (ALS) was a disease with no treatment. Within five years, most people with ALS would experience progressive muscle weakness, paralysis and eventually respiratory failure. 

Then in 2023, the Food and Drug Administration (FDA) approved Qalsody for treating a rare form of ALS linked to a mutation in the SOD1 gene, showing it might be possible to slow the disease. 

Since then, researchers have scoured the genome to understand the role of genetic factors and perhaps find new drug targets for ALS. A recent study published in Nature Genetics strengthens the evidence for known genetic risk factors and uncovers a few new risk factors as well. 

More than 20 percent of the almost 18,000 participants with ALS had at least one such genetic risk factor, and many had multiple. 

“The genetic variants that contribute to the disease tend to be a lot rarer than than is the case for other disorders, but they’re also a more potent, and strongly influence disease risk,” study author Kevin Kenna, a neurogeneticist at UMC Utrecht in the Netherlands, told Being Patient. 

Because of their strong link to the disease, the recently discovered variants “provide new clues to the mechanisms at play in ALS,” he said.

Searching for genetic risk factors for ALS

Kenna and his colleagues conducted one of the largest studies to date, analyzing the genes of 17,919 people with ALS and 200,703 matched controls. 

Each gene is encoded by a combination of four genetic letters called basepairs. Deleting or substituting one letter for another could alter the instructions for making a protein, meaning one tiny change could alter important cellular processes. Kenna’s time looked for specific variants that were much more common in people with ALS than in the healthy controls to tie those changes to the disease. 

As expected, several previously identified genetic variants like SOD1 and FUS, which are known to increase ALS risk, popped up in the analysis. They confirmed that other genes, where previous evidence of their potential risk was limited, also increase the likelihood of developing ALS like ARPP21. Then, they found a handful of new genetic risk factors like YKT6, HTR3C, GBGT1 and KNTC1. 

The risk factors varied in their strength. For example, those with a rare SOD1 variant are 200 times more likely to develop ALS, and those with an ARPP21 variant are 40 times more likely. Having multiple genetic risk factors may have an additive effect, making it even more likely that someone develops the disease. Another variant of ARPP21 was also linked to earlier onset and faster progression. 

Kenna said this information could be useful for genetic counselors, providing patients and families more information about their prognosis.

Among the newly discovered genes, Kenna is particularly interested in those that play a role in the cytoskeleton — the cellular highways that carry important materials throughout the cell. “I think these new genes will help build new models to help dive into some of those questions in more detail,” said Kenna.

Stanford genetics professor Michael Snyder, who wasn’t involved in the study, called the findings important. “What people don’t realize is that a lot of ALS is heritable,” he said, and finding the genes strongly linked to the disease is the first step toward tailored treatments. 

From genes to new treatments

Using the genetic risk factors, scientists can already screen for new drug targets. U.S.-based initiatives like n-Lorem “are working on building pipelines for genetic targeting of individual mutations,” said Kenna. 

Snyder’s lab, which also looks for new ALS variants, uses an artificial intelligence-powered approach to spot these risk factors. 

When they spot one of these genes in an individual, they grow their cells in a Petri dish. Then they develop anti-sense oligonucleotides (ASOs), small bits of DNA designed to target and prevent specific genes from making proteins, to see if it might fix some of the cellular dysfunction. The successful ASOs could then be tested in trials. 

ASOs have already made it to trials for neurodegenerative disease. Biogen’s BIIB080 is in a Phase 2 trial to see if it could treat Alzheimer’s by slowing tau formation.

Although the work of translating these genetic discoveries into new medicines is promising, Kenna is also careful not to oversell the promise. Though it’s a major step forward, it may be a while before new treatments targeting these genes, the processes they affect, make it to human trials.