Research Update, August 2025

Breaking down the breaking news: Researchers at the Sunnybrook Health Sciences Centre are testing a new technology to noninvasively deliver treatments through the blood-brain barrier*, using a focused ultrasound procedure that opens small spaces in the barrier to let treatments cross into the brain. The team is testing the procedure in a small clinical trial with six participants, aiming to evaluate the safety and biological effects of this technique. They have already successfully administered an immunoglobulin (IVIG) treatment to the motor cortex of one person living with ALS. If successful, the technique could potentially be used to enhance the delivery of promising therapies in the future, offering hope for more targeted ALS treatments.

* The blood-brain barrier (BBB) is a protective layer that controls what can pass from the bloodstream into the brain, allowing in essential nutrients while blocking out harmful substances like toxins and bacteria. While this barrier is crucial for keeping the brain safe, it also makes it difficult for most drugs to reach the brain, which is a challenge for treating ALS.

Breaking down the breaking news: In this article, results from the Phase 2 MIROCALS trial are discussed. The trial was investigating low-dose interleukin-2 (IL2_LD), a treatment targeting the immune system. Overall, the trial did not show a significant survival benefit. However, further analyses of the data showed that it may offer a benefit for individuals with slow disease progression, but not for those with faster progression. Despite being a long clinical trial with a large number of participants, another study will likely be required to better understand the effect of IL2_LD.

Our colleagues at the Motor Neurone Disease Association have written a detailed and realistic blog about the results here: MIROCALS: breaking down the trial results.

Breaking down the breaking news: Read about Daniel Knight, an early-career investigator whose lab is funded by the ALS Canada Research program.

Read more on his lab’s project here.

In this project, early-career researcher Farbod Khorrami and Dr. Yeni Yucel’s team (University of Toronto) aimed to identify a novel biomarker* for ALS through ocular imaging. Using mouse models mimicking aspects of ALS, they examined retinal ganglion cells (RGCs), which can be studied non-invasively, unlike motor neurons in the brain. Through eye exams, the team looked for hyperreflective puncta, which are small, bright spots seen in the retina during optical coherence tomography (OCT) imaging. These features are believed to be indicative of inflammation and underlying signs of some diseases. This was the first study to verify that ALS mice had a significantly higher number of puncta in the retinal nerve fiber layer (RNFL) compared to control (healthy) models. An increase in the number of puncta also correlated with age, with female mice showing a greater increase.

In addition, the team also looked at axonal spheroids, which are bubble-like features that are formed when a part of a neuron called the axon becomes damaged. These spheroids are commonly found in motor neurons in the brains and spinal cords of people living with ALS. The team also demonstrated the presence of axonal spheroids in the RGC axons of ALS mice, showing promise that the eye could be used to track this damage. Further research is needed to explore these findings, investigate potential sex-differences, and translate these methods to humans. If successful, this project could establish safe, non-invasive, rapid, and relatively inexpensive biomarkers for ALS which could be used to support disease monitoring and track progression. Learn more about some of the researchers behind it here.

* Biomarkers are biological measures that provide real-time insights into processes happening in the body and tell us information about a person’s health status. As an example, the level of cholesterol in the blood can serve as a biomarker for the risk of heart disease. Existing experimental biomarkers for ALS are often expensive, invasive, or not easily accessible by clinicians and patients. Thus, there is an urgent need for accurate and accessible biomarkers within the field to diagnose ALS, track progression of the disease, and measure response to potential therapies in clinical trials.

In this study, Dr. Maria Boido (University of Turin, Italy) and team aimed to investigate if chronic stress can exacerbate ALS symptoms and affect disease progression in animal and cellular models that mimic ALS. The laboratory models studied included SOD1 mice, as well as three different cellular models: mouse motor neurons expressing an SOD1 variant; human motor neurons with a TARDBP (TDP-43) variant; and healthy control motor neurons for comparison. The mice were exposed to a month-long stress routine, while the cells were stressed by limiting their oxygen and sugar supply.

In the mice, both males and females showed significantly reduced weight gain, while only the females experienced noticeable declines in movement. This is relevant as malnutrition and weight loss are widely recognized as poor prognostic factors in ALS. Researchers also found that stress altered the expression of key genes and proteins involved in inflammation, cell survival, and structural stability. These changes were linked to disrupted PI3K/Akt and focal adhesion pathways, both crucial signalling pathways that help cells respond to their environment and maintain healthy function. These pathways are already established in cellular stress responses, but more research is needed to better understand their role in ALS specifically. Notably, SOD1 cell models showed signs of cellular stress and death even without added external stress, suggesting increased vulnerability to additional environmental factors.

The relationship between stress and ALS has been explored for decades, but it remains complex and further studies are needed to confirm its role in disease. This specific study contributes to growing evidence that stress may impact disease progression, particularly in individuals with a genetic predisposition to ALS. Moreover, examining the affected pathways in this experiment could reveal potential targets for new treatments.

Jacifusen is an antisense oligonucleotide therapy being investigated for FUS-ALS, aiming to reduce FUS* protein levels. It works similarly to the newly approved therapy targeting SOD1-ALS (Qalsody), which is effective for people with an SOD1 gene variant. Results from an expanded access program (EAP) reported that jacifusen was generally well tolerated and reduced neurofilament light (NfL)** levels by up to 82% in most of the 12 participants treated over six months. While most participants continued to decline according to the ALSFRS-R scale, one participant showed notable functional recovery after 10 months, and another, treated presymptomatically, has not developed symptoms over three years of treatment. The FUSION clinical trial (with jacifusen now called ulefnersen) is currently underway in hope of providing conclusive evidence as to whether the treatment is effective or not in people with FUS-ALS.

* The FUS gene contains the instructions to make a protein called fused in sarcoma (FUS). In ALS, researchers have discovered that variants in the FUS gene lead to the creation of a defective FUS protein, causing toxicity to motor neurons. FUS variants cause about three to six per cent of familial ALS cases and are found in about one per cent of individuals with no obvious family history.

** NfL is an essential building block of nerve cells, and elevated levels of NfL in bodily fluids (such as blood or cerebrospinal fluid) can indicate damage or death of these cells. NfL is now recognized as one of the most important biomarkers for ALS.

In this study, Dr. Lilian Lin (University of Toronto) and the Robertson lab reveal evidence that C9orf72 deficiency worsens ALS-related features in mouse models of the disease. Variants in the C9orf72 gene have long been established to lead to an increased risk of ALS; however, there are opposing theories about whether C9orf72 variants cause a gain or loss of function. This means that when a variant in a gene causes ALS, it may do so by either reducing the normal function of the resulting protein (loss of function), by giving the resulting protein a new toxic function (gain of function), or in some cases, both. This study supports the hypothesis that C9orf72 has loss-of-function features, contributing to neurodegeneration in people affected by ALS or frontotemporal dementia (FTD) linked to a C9orf72 variant. The team specifically found that when C9orf72 is missing, harmful TDP-43* fragments (especially one called TDP-25) lead to severe motor problems and loss of brain cells. Additionally, the deficiency seems to disrupt autophagy, which is a “self-cleaning” process that breaks down and clears out cellular waste, like dysfunctional TDP-43/TDP-25 so the cell can function properly.

It is extremely important to understand the function of the C9orf72 gene so targeted genetic therapies can address the loss- or gain-of-function effects, bringing us closer to a novel treatment. The Robertson lab, led by Dr. Janice Robertson, has been supported multiple times through the ALS Canada Research Program. You can find a database of our funded projects here.

*It is known that most ALS cases have abnormal TDP-43 biology, regardless of a genetic variant. TDP-43 is a protein that plays many roles in gene regulation, RNA and protein biology, and normal cell function. TDP-43 is typically found in the nucleus of the cell, which houses DNA, but in most cases of ALS, the protein ends up in the cytoplasm (the portion of the cell outside of the nucleus) and can form clumps called aggregates. Researchers are working to understand whether abnormal TDP-43 affects motor neurons due to a loss of its normal function in the nucleus, an extra toxic function in the nucleus or cytoplasm, or a combination of these.

Breaking down the breaking news: This article explores advancements from a brain-computer interface (BCI) being investigated in the BrainGate2 clinical trial. You can read our Inside the Science blog to learn more about how BCI works in ALS, as well as our previous research update on the technology.

New ALSUntangled review exploring alpha-lipoic acid (ALA) as an off-label treatment for ALS. Given insufficient clinical data, ALSUntangled cannot endorse ALA and supports more research on its efficacy in slowing ALS progression.

In this publication, ALS Canada-funded researcher Dr. Matti Allen (McGill University/University of Ottawa) and team discuss the need for a standard version of the self-administered ALS Functional Rating Scale–Revised (ALSFRS-R)* to be used consistently across all clinics and clinical trials worldwide. Although the ALSFRS-R is considered the gold standard for measuring ALS progression, inconsistencies in descriptions, languages, and the platforms used over time can decrease the reliability of the data, especially in research settings. A recent initiative has led efforts toward further harmonization and training on the scale worldwide. However, difficulties remain, especially for the self-administrated version, which has gained popularity due to its ability to collect data remotely and more frequently than in-clinic assessments. Dr. Allen reviewed multiple studies and highlighted the need for harmonizing a self-administered ALSFRS-R, outlining next steps toward developing a digital, multilingual version that can be used globally.

* The ALSFRS-R is a widely used clinical tool to measure disease progression in people living with ALS. It evaluates a patient’s ability to perform everyday tasks and tracks decline over time. Through a structured interview, the clinician or patient assesses bulbar symptoms, fine and gross motor function, respiratory symptoms, and the need for ventilation or feeding tubes. You can access the scale here.

This aligns with another recent study: “Integrating Multi-sensor Time-series Data for ALSFRS-R Clinical Scale Predictions in an ALS Patient Case Study,” where Dr. Noah Marchal (University of Missouri) and team explored how in-home sensor data could be combined with clinical assessments to better track ALS progression in a person living with ALS. Sensors were installed in the participant’s bed and throughout the home, capturing data on movement, breathing, and sleep. Using machine learning, the researchers aimed to identify personalized models to predict changes in functional abilities, such as speech, swallowing, and motor tasks, based on the sensor inputs. They found that some functions could be predicted with just a few features, while others required more complex data. The researchers argue that sensor-based tools show promise in enabling more frequent and precise monitoring of ALS outside of the clinic. Additional participants are being recruited to validate and refine these models.

In this publication, Dr. Angela Genge (Montreal Neurological Institute and Hospital) and team investigated the long-term safety and side effects of oral edaravone over a period of 1 year and 10 months. The results indicated that the drug continues to be well tolerated, and the most common treatment-emergent adverse effects* were falls, muscular weakness, shortness of breath, constipation, and difficulty swallowing. Studies like these are important to investigate drugs over a longer period than typical clinical trials, and in real-world settings.

*A treatment-emergent adverse effect (TEAE) is any unwanted or harmful event that either starts after a treatment begins or gets worse in intensity or frequency compared to how it was before the treatment started. They may or may not be caused by the treatment. 

In this study, Dr. Daniel Saucier and team in New Brunswick aimed to investigate the association between long-term exposure to various air pollutants and the development of ALS. The odds of developing ALS were significantly associated with long-term exposure to SO₂ (sulfur dioxide, commonly produced from fossil fuels and industrial processes). NO₂ (nitrogen dioxide), ozone, and fine particulate matter (such as dust, soot, smoke, or other chemicals) did not show a significant association. The study analyzed data from 304 ALS cases and 1,207 matched healthy control cases. The authors note that more research is needed to determine if SO₂ exposure is a key causal or contributing factor for the development of ALS, or if it potentially accelerates a neurodegenerative process already taking place.

! Important note on interpreting the findings: The study above identifies an association between two factors (air pollution and ALS), not causation. This means the study shows a statistical relationship but cannot prove that one factor directly causes the other. Observational studies like this are limited by potential confounding factors, biases, and gaps in the data. To determine causation, researchers must conduct controlled experiments, like randomized clinical trials, that can rule out other explanations. However, these studies are valuable for identifying possible environmental risk factors and guiding future research into ALS causes and prevention.

Read more about environmental factors and ALS here.