ALS researchers from around the world continue to build upon existing work and make new discoveries in the hopes of realizing a future without ALS. In the July 2023 Research Update, you’ll learn about the role genetic factors may play in sporadic ALS, a promising new treatment target, a new tool to measure disease progression more accurately, recent advances in the clinical understanding of ALS, and more. 

We recently developed a research glossary that contains a list of scientific and medical terms and definitions relevant to ALS. The glossary was created to support knowledge-sharing by helping to provide clarity around terminology that may be unfamiliar to our readers. Click here to download a copy.  

New insights into the genetic variability of sporadic ALS 

Pink graphic of dna piece

Multiple large-scale studies further demonstrate that genetic factors play a role in sporadic (non-inherited) ALS cases.  

Approximately 10% of individuals with ALS have a family history of the disease. In these cases, often termed familial ALS, the disease is caused by a change in the genetic code, called a mutation or variant, and can be passed from parent to child. The remaining 90% of individuals without a family history are said to have sporadic ALS, however, emerging evidence suggests that a portion of these individuals may also carry mutations in known ALS genes. 

A pair of recent studies set out to better understand the genetic contribution to sporadic ALS using a technique called whole genome sequencing, which gives scientists the ability to read a person’s complete set of DNA – all 3.2 billion building blocks! In the first study, samples from 6,013 sporadic ALS patients and 2,411 healthy controls were analyzed. Researchers found that known ALS genetic mutations were present in 11% of the sporadic cases studied, and that these mutations were linked to 38 different genes. In the second study, researchers tested samples from 2,267 sporadic ALS patients and again found that a significant proportion, approximately 13%, carried a known genetic mutation linked to ALS. 

Another study with a slightly different approach specifically looked for rare genetic defects, called short tandem repeat expansions, that have been linked to more than 20 different neurodegenerative diseases. After analyzing samples from 608 sporadic ALS patients, researchers found that almost 18% carried these rare DNA repeat expansions. This suggests there may be common risk factors and shared mechanisms leading to neuronal death among the various diseases, and potentially opportunities for shared therapeutic strategies in the future. The researchers note, however, that larger studies are required to determine the true significance of these repeat expansions to disease.  

Taken together, the results from these studies further support the idea that genetic factors play an important role in sporadic ALS cases. With recent advancements in targeted genetic therapies, such as tofersen (Qalsody), which was recently approved by the FDA in the U.S. to treat SOD1-linked ALS, these studies also emphasize the importance of offering genetic testing to all people living with ALS.  

Identification of an immune protein as a promising treatment target for ALS

Researchers have identified a new cellular target that could help to slow neurodegeneration and treat ALS. 

Gasdermin-E (GDSME) is a protein typically involved in the immune response and is expressed in nerve cells in the brain. Up until now, however, that was all that was known about GDSME. To better understand the function of this immune protein, a team of researchers developed cell and animal models to study how GDSME affects neurons. They found that when activated, GDSME caused damage to various cellular structures, such as mitochondria (the powerhouses of the cells) and axons (the long cable that carries electrical signals along the length of a motor neuron).  

To determine the relationship between GDSME and neurodegeneration, researchers studied motor neurons derived from people living with ALS and found that the protein was present at higher levels. When GDSME was removed from these neurons, the damage to mitochondria and axons was significantly reduced. To validate these findings in a more complex system, researchers created an ALS mouse model that could not produce the GDSME protein and found that this delayed the progression of symptoms, led to protected motor neurons with longer axons, and reduced overall inflammation.  

Ultimately, these findings suggest that GDSME drives changes to neurons that may contribute to disease progression. It remains unclear what role GDSME may play in heathy brains, meaning that more studies are required to determine how easily or safely it could be targeted without causing other side effects, but this work is an important first step in identifying a promising new treatment target for ALS. 

A new tool to measure disease progression more accurately in ALS 

A team of researchers have developed a new tool, called the ALS Impairment Multidomain Scale (AIMS), that may be able to better characterize ALS disease progression when compared to currently available methods used in clinical trials. 

The revised ALS Functional Rating Scale (ALSFRS-R), a 12-item questionnaire that assesses function in certain daily activities, is most commonly used to evaluate disease severity, monitor disease progression and serve as an outcome measure in ALS clinical trials. One of the major limitations of the ALSFRS-R, and similar tools like the Rasch-Built Overall ALS Disability Scale (ROADS), is that answers from the different domains (bulbar, motor, respiratory, etc.) are all combined into one total score. This can be problematic because two people with the same total score may not be comparable with respect to their symptoms, disease stage, or prognosis, which complicates assessment of disease progression and can make observing treatment effects in clinical trials more difficult. 

In this study, researchers set out to develop a scale that can better characterize disease progression. A preliminary questionnaire was created based on a literature review, international guidelines for ALS, the clinical judgement of a panel of experts, and patient input. The preliminary questionnaire consisted of 110 questions and was completed by 367 people living with ALS. In the end, after optimization and refinement, three subscales were included consisting of 7 bulbar (speech/swallowing), 11 motor and 5 respiratory questions. Validation studies showed that the AIMS subscales are reliable, optimized to measure disease progression, and strongly related to survival time.  

Researchers are hopeful that the easily administered AIMS represents a promising new outcome measure for use in the clinic and clinical trials, that may be more sensitive than currently available methods for monitoring disease progression, ultimately increasing the likelihood of identifying effective treatments in future ALS clinical trials.  

Canadian researchers further contribute to the clinical understanding of ALS 

Canadian ALS researchers continue to make significant contributions to the global understanding of ALS. Below are just two examples of the innovative discoveries that Canadians have made this year.

A study emerging from the Canadian ALS Neuroimaging Consortium (CALSNIC) reveals that reduced levels of N-acetylaspartate (NAA), a neurochemical associated with healthy neurons, may be an early indicator of communication issues within the brain that are thought to contribute to ALS. For this study, 52 people living with ALS and 52 healthy controls were enrolled at five sites across Canada. Results from magnetic resonance imaging (MRI) scans were combined with tests measuring neurochemical levels in the brain and clinical assessments measuring motor function (such as foot tapping, for example). 

Researchers found that a drop in NAA levels was associated with loss of motor function and a breakdown in the connection between the primary motor cortex — the part of the brain that controls our muscles — and other brain regions in people living with ALS. The results from this study suggest that measuring NAA levels could serve as an effective biomarker for early brain changes associated with ALS and assist with earlier diagnosis of the disease. The researchers note, however, that more studies are needed to better understand exactly how NAA levels may influence loss of function, and how this may impact future treatment strategies. 

A second study aimed to pinpoint the acoustic characteristics associated with bulbar and pre-bulbar ALS in Canadian French speaking individuals. Previous research has shown that artificial intelligence (AI) algorithms can be trained on voice recordings from English speaking ALS patients to detect speech abnormalities, in some cases even prior to the onset of any clinically detectable bulbar symptoms. Here, researchers apply this methodology to Canadian French speakers, with the goal of being able to distinguish ALS patients from healthy controls based on speech features alone. 

As part of this study, a total of 29 French speakers with ALS and 17 healthy controls were asked to complete reading passages. Certain speech characteristics were measured and analyzed, such as speaking rate, total duration, and pause events. Researchers found that a combination of these measures would be optimal for detecting and monitoring bulbar symptoms in French speakers with ALS, but they caution that more work is required to identify which measures are sensitive to the earliest stages of the disease. This work is of high importance to French speaking Canadians with ALS, as outcomes from this study could improve standard of care and access to clinical trials. 

Advancing our understanding of the biological pathways that contribute to motor neuron health 

Using cell and animal models, scientists study the effects of known ALS-causing mutations in the laboratory, providing new insights into the biological pathways that contribute to disease.  

Recent technological advancements have made it much easier for researchers to conduct large scale genetic studies. The first gene identified as being linked to ALS was SOD1 back in 1993. In the 20 years since then researchers have identified more than 90 different ALS-linked genes, and with each one comes a new understanding of the biological pathways that lead to disease. One extremely useful way to investigate the downstream effects of these gene mutations is through the use of animal models that attempt to replicate disease. 

In 2018, two different studies (1,2) revealed that mutations in KIF5A, a protein that plays an important role in the transport of cellular cargo from one end of a motor neuron to the other, were linked to ALS. However, exactly how these mutations contribute to disease was not known. In a recent study, researchers produced a new mouse model of a KIF5A mutation using a modern gene-editing technique called CRISPR. Although these mice did not display the typical functional loss observed in ALS, researchers found that their motor units (which consist of a motor neuron and the muscle fibers it interacts with) showed signs of impaired recovery after injury. Additionally, as the KIF5A mice aged, the number of motor units decreased more than expected, suggesting that over time mutations led to decreased maintenance and resilience of these important structures. Ultimately, the findings led researchers to conclude that KIF5A mutations may make people less susceptible to dealing with biological challenges such as injury and aging, which negatively influences motor unit maintenance and repair, ultimately leading to disease. 

In a separate study, researchers created cellular models of another known ALS-linked gene, called CCNF. Mutations in CCNF are thought to disturb the ubiquitin-proteasome system (UPS), an important cellular process that involves the labelling of a misfolded protein with a small tag called ubiquitin that serves as a signal to the cell to degrade the protein. Using induced pluripotent stem cells (iPSCs), an invaluable tool when studying neurodegenerative disease in the laboratory, researchers confirmed that CCNF mutations do cause UPS dysfunction within cells, reinforcing the notion that this system may play an important role in the onset/progression of ALS. 

The results from both studies highlight the importance of creating complex models in the laboratory to study ALS. Insights gained from these types of studies help researchers to better understand the underlying biology and mechanisms that contribute to ALS, which forms the foundation for identifying new treatment targets. 

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. 

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