ALS Research Update, August 2020
The ALS Canada Research Program is encouraged by the continued momentum seen in ALS research at a time when support for it is more important than ever before. Read about the progress researchers have made in advancing new treatment strategies, understanding the effectiveness of riluzole in the real world; and learning how ALS develops and progresses in the body.
Real-world evidence provides new insights into the effectiveness of riluzole for treating ALS
New data suggests that treatment with riluzole may prolong survival in people living with ALS by 6 to 19 months, which is much longer than the 2 to 3 months reported in past clinical trials.
In 2000, Health Canada approved riluzole for the treatment of ALS. The exact mechanism by which riluzole works is still unknown, but researchers believe that it may reduce damage caused to motor neurons by a specific excitatory signal in the brain as well as possibly reducing the TDP-43 pathology observed in almost all ALS cases.
Within the scientific community, clinical trials are considered the gold standard in determining if a drug is safe and effective. There are often strict criteria in place for who can participate in a clinical trial. This is required in order to properly evaluate a drug, however, it can also limit the applicability of the results to a broader patient population.
In a new study, researchers used real-world evidence, also known as population studies, to determine how well riluzole works in a wider range of people living with ALS than would have been included in the earlier clinical trials. The researchers identified 15 population studies that compared groups of people treated with riluzole to those who were untreated. Overall, the data showed that riluzole may help to extend survival by 6 to 19 months.
The researchers note that this real-world evidence provides additional insights into the benefits of early use and long-term effectiveness of riluzole. This positive data should help guide treatment decisions for people living with ALS, as well as influence drug coverage policies and reimbursement pathways.
The gut microbiome may influence disease severity in people with a genetic form of ALS
A new study shows that bacteria found in the gut may influence disease onset and progression in people who carry C9ORF72 mutations, the most common genetic form of ALS.
The gut microbiome is the natural collection of microorganisms (bacteria, viruses, fungi, etc.) that live in our gastrointestinal tract. The gut microbiome plays an important role in nutrient and mineral absorption, as well as overall gut health. Recently, however, increasing evidence suggests that the gut microbiome can also play a role in one’s susceptibility to diseases, including those of the brain.
By studying mice with reduced C9ORF72 levels, researchers at Harvard University found that the environment the mice were raised in can change the composition of their gut microbiome, which in turn can affect inflammation levels within the brain and overall survival. The study, which was recently published in the journal Nature, suggests that reducing levels of bacteria that promote inflammation may be protective and can reduce disease severity.
Identifying environmental factors that can potentially delay the onset or modify the course of ALS is of great interest to the scientific community. The researchers note that an important next step will be to identify people who carry C9ORF72 mutations and determine whether the gut microbiome is different between those that develop ALS and those who do not.
A diabetes medicine shows early signs of promise in treating C9ORF72-linked ALS
Scientists have shown in mice that a common diabetes drug, called metformin, can reduce levels of specific toxic proteins thought to play a role in the onset and progression of C9ORF72-linked ALS.
Within cells, C9ORF72 mutations lead to the production of destructive proteins called DPRs. These DPR proteins tend to clump together in cells and accumulate within the central nervous system of patients with this genetic form of the disease.
In the study, mice carrying a mutant C9ORF72 gene treated with metformin showed decreased levels of these toxic DPR proteins. Compared to their counterparts that were not given the drug, these mice showed improvements in behaviour and movement, as well as reduced inflammation in the brain and increased survival of motor neurons.
The next step is to confirm whether the positive results from these mice studies can be replicated in humans. A small Phase 2 clinical trial is currently underway at the University of Florida to determine if metformin is safe for patients with C9ORF72-linked ALS and whether the drug can reduce DPR protein levels in humans. If it proves to be successful, researchers plan to move the drug forward to a larger, placebo-controlled trial.
Exploratory research into a gene silencing approach to treat SOD1-linked ALS
Preliminary findings suggest that a new gene silencing technique could be used as a potential treatment for a familial form of ALS, resulting from mutations in the SOD1 gene.
Approximately 20 percent of inherited cases of ALS result from mutations in the SOD1 gene, as well as a small percentage of sporadic cases. It is thought that mutations cause the SOD1 protein to fold into the wrong 3D shape, a process referred to as misfolding, which can cause it to gain a toxic function within motor neurons.
In a proof-of-concept study, recently published in the New England Journal of Medicine, researchers developed something called microRNA, which binds to SOD1 mRNA (the blueprint used to create the SOD1 protein in cells) and thereby prevents formation of the toxic protein, in a process known as “silencing.” The theory behind this approach is that if researchers can reduce levels of the toxic SOD1 protein within the body, they may be able to slow or even stop the progression of ALS.
As part of the study, two ALS patients received a single dose of the microRNA which was delivered directly to the spinal fluid through what is called an intrathecal injection. The microRNA was attached to a harmless virus to ensure it was delivered directly into cells where it could prevent production of the SOD1 protein. The results showed that the microRNA was able to reduce SOD1 levels in spinal cord tissues.
Alternative methods aimed at reducing SOD1 levels within the body are currently under investigation in late stage clinical trial and show promise. However, one advantage to the method described above is that a single dose of the microRNA may have long-lasting effects, whereas repeated dosing is often required with other approaches. The researchers are encouraged by these early results, noting that the next step is to test the effectiveness of the microRNA in a larger clinical trial of participants with SOD1 mutations.
The role of POM121 in altered nucleocytoplasmic transport in C9ORF72-linked ALS
New research provides insight into a mechanism behind the disrupted nucleocytoplasmic transport (NCT) observed in C9ORF72-linked ALS.
NCT involves the exchange of substances between two important compartments of the cell, the nucleus and cytoplasm, and is crucial to cell survival. Growing evidence suggests that NCT in cells is disrupted as a result of mutations in C9ORF72. The mechanism for this disruption, however, remains unknown.
A new study, published in the journal Neuron, revealed that NCT disruption may be linked to a specific protein called POM121. Using advanced high-resolution technology, researchers were able to visualize the nucleus of neurons derived from stem cells in the laboratory. They found that mutations in C9ORF72 led to a reduction in POM121 levels, which in turn affected the levels of seven other proteins that play an important role in NCT within cells.
The researchers conducted further analyses to determine what was causing POM121 levels to decrease. Previous studies show that mutations in the C9ORF72 gene can cause reduced levels of the C9ORF72 protein, as well as lead to the production of two toxic substances – . The researchers found that only the repeat RNA molecules led to a reduction in the POM121 levels.
Overall, the data suggests that the repeat RNAs produced from mutations in C9ORF72 may play an early role in the cellular dysfunction that leads to ALS. This is another important piece of the puzzle that will help researchers to better understand the biological pathways responsible for this disease, which is crucial to being able to develop effective treatments.
Bringing you the latest news on advancements in ALS research, the ALS Canada research team regularly summarizes the most significant discoveries throughout the year.
Note: We have included links to the publications because we know you may be interested in the original source papers. While abstracts are always available, many journals are subscription based, and in some cases, full papers may only be accessed at a cost.