While 2020 has been an unpredictable and challenging year on many fronts, the ALS Canada Research Program continues to observe positive momentum in ALS research. This month you’ll learn about results from two different Phase 2 clinical trials in ALS; the normal function of the C9ORF72 protein; the role of perisynaptic Schwann cells at the neuromuscular junction; and how mutations in the C9ORF72 gene may impact the immune system.

Experimental treatment for ALS shows promise in Phase 2 clinical trial

Results from a large Phase 2 clinical trial show that reldesemtiv, a muscle-activating drug being developed by the pharmaceutical company Cytokinetics, may help to slow rates of decline in ALS.

This trial enrolled 458 participants from centres across Canada, the U.S.A., Europe and Australia. Participants were randomly assigned to receive either reldesemtiv (at varying doses) or placebo, for 12 weeks. Throughout the trial, researchers monitored participants for changes in slow vital capacity (SVC), a measure of lung function, as well as ALS Functional Rating Scale-Revised (ALSFRS-R) scores and muscle strength.

The study results were recently published in the journal Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and showed that overall reldesemtiv was well tolerated by participants, with the most commonly reported side effects being nausea and fatigue. When compared to those on placebo, participants receiving the active drug appeared to have slower rates of decline across multiple measures of ALS progression; including a 27% reduction in SVC decline and a 25% reduction in ALSFRS-R decline. It is important to note though that these measures did not reach statistical significance, meaning the researchers cannot be certain that the differences observed between the two groups (active drug vs. placebo) are real and not due to chance.

Regardless, the researchers believe these results are promising and clinically important, and as such support the decision to move reldesemtiv forward to a larger confirmatory Phase 3 clinical trial. A previous Phase 3 clinical trial of another muscle activating drug developed by Cytokinetics, called tirasemtiv, did not have a positive outcome, however, participant dropout due to side effects was a significant issue in this study. Reldesemtiv is a second-generation muscle activating drug, with reduced side effects, so we are hopeful for a better outcome in this case.

A new drug combination may help to slow functional decline in ALS

A study recently published in the New England Journal of Medicine shows that AMX0035, an experimental therapy being developed by the pharmaceutical company Amylyx, has promise for slowing the progression of ALS.

AMX0035 is an oral drug that contains two small molecules which are thought to help preserve motor neuron health and thereby delay the progression of symptoms in people living with ALS. The Phase 2 study was held in various states across the U.S.A. and enrolled 137 participants who were measured and assessed over a 24-week period, primarily based on the ALS Functional Rating Scale-Revised (ALSFRS-R). The

results showed that AMX0035 was safe and slowed functional decline by approximately 25% in participants receiving the active drug when compared to those on placebo.

The preliminary data also showed potential benefits in other areas, such as measures of muscle strength, breathing and hospitalization frequency. Many participants in the trial , meaning that the effects of AMX0035 observed in this study were in addition to that for the current standard of care. A follow-up study on long-term data from the clinical trial and its open-label extension was published in the journal Muscle & Nerve. The results demonstrated that early treatment with AMX0035 also showed potential for extending survival in people living with ALS.

While these results are a step in the right direction, the researchers noted that longer and larger clinical trials may be necessary to better evaluate the safety and effectiveness of AMX0035 in people living with ALS. ALS Canada has been in contact with Amylyx for many years and continues to advocate to have Canada included as a location for clinical trials and regulatory approval (if applicable).

High resolution data gives clues to the normal function of C9ORF72

New data shed light on and provide a strong foothold for better understanding the normal role of C9ORF72 in important cellular processes, and how the loss of these functions may contribute to disease.

In 2011, scientists discovered that mutations in the C9ORF72 gene are the most common genetic cause of ALS. These mutations result in reduced levels of normal C9ORF72 protein within cells, while also promoting the formation of additional toxic substances. But exactly how these changes contribute to causing ALS is not fully known. To determine how reduced levels of C9ORF72 protein may cause disease, researchers must first understand its normal function.

In a new study recently published in the journal Nature, researchers used a technique called cryogenic electron microscopy, a method that allows them to visualize protein structures at high resolution, in order to view the structure of the C9ORF72 protein. By studying how the protein interacts with two additional proteins, the researchers were able to gain insights into the roles of C9ORF72 in lysosomal signaling (a pathway by which cells recycle and pool valuable building blocks required to function) and autophagy (the process by which cells degrade unnecessary or dysfunctional components). Both processes are vital for cell survival.

The results from this study are an important step forward as in order to develop effective treatments for this form of ALS, researchers will need to be able to address the consequences of reduced C9ORF72 levels as well as those from the toxic substances produced.

New insights into the interplay between C9ORF72 and the immune system in ALS

Study findings suggest that mutations in C9ORF72, the most common genetic cause of ALS, may lead to an altered immune response in people living with this form of the disease.

When a person is infected by a foreign invader, such as a virus, it triggers an immune response that generally results in inflammation. For example – think of a sore throat and the redness and swelling that occurs when you are sick with tonsillitis. The immune response is designed to rid the body of the pathogens causing the infection, but sometimes our own cells can be damaged in the process. As such, the body has mechanisms in place to ensure the immune response does not become overactive, which can be dangerous.

Mutations in the C9ORF72 gene result in a lack of functioning C9ORF72 protein within cells. In a new study recently published in the journal Nature, researchers used a mouse model of ALS to analyze the effect of reduced C9ORF72 levels in specific immune cells. They found that lower levels of the protein resulted in increased inflammatory activity. More specifically, the lack of C9ORF72 prevented the breakdown of a protein called STING, which acts as a signal to activate the immune response.

These data suggest that people with C9ORF72-linked ALS may have an altered immune response because reduced C9ORF72 levels mean they cannot suppress inflammation as well as those with normal levels.  Researchers note that this may help to explain why people with ALS are more likely to develop autoimmune disorders (which occur when a person’s immune system attacks its own healthy cells) compared to the general public. Strategies to better regulate the altered immune response in people with C9ORF72-linked ALS may also help to reduce inflammation within the nervous system, which is thought to be a factor in the progression of ALS.

Mouse models reveal that specialized support cells may be defective in ALS

Early data suggest that specialized support cells within the peripheral nervous system, called perisynaptic Schwann cells (PSCs), do not function properly in ALS.

One of the earliest signs of disease in animal models of ALS is disruption at the neuromuscular junction (NMJ) – the place where neurons connect to muscle. PSCs are critical for maintaining this connection and oversee repair of the NMJ when damage occurs.

In a new study published in The Journal of Neuroscience, researchers explored whether PSCs can repair damaged NMJs in ALS using mouse models of the disease. The results showed that communication between neurons and PSCs is disrupted in these mice, which prevents PSCs from taking on their repair role. This altered response may contribute to the vulnerability of the NMJs in ALS.

The researchers noted that further studies aimed at better understanding the mechanism behind the altered PSC response may reveal novel targets for treating ALS. Restoring the repair capabilities of PSCs could help to stabilize the neuron-muscle connection at the NMJ and improve functional abilities in people living with ALS. The lead author for this study, Dr. Éric Martineau, was previously supported by ALS Canada through a Doctoral Research Award in 2015.

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.

Posted in: Research, Update