Fundamental Research Update, July 2026

*A common feature in most ALS cases is a disruption of the normal function of a protein called TDP-43. This protein is found primarily within the nucleus of a cell, where it helps to regulate essential cell processes, but in ALS, it becomes trapped outside in the cytoplasm forming clumps or aggregates. These clumps, and the loss of TDP-43 cellular function, are theorized to contribute to motor neuron damage and death. Because of this, treatments aimed at preventing TDP-43 from being trapped outside of the nucleus or clearing TDP-43 clumps could offer a possible way to slow or stop ALS progression. 

Researchers are continuing to explore whether statins, commonly used cholesterol-lowering medications, could have benefits beyond heart health in ALS. Previous studies have produced mixed findings, making this an area that requires further investigation.

Why is STMN2 important?

One reason statins have attracted recent interest is their potential impact on STMN2, a protein that helps motor neurons grow, maintain, and repair their connections. In most cases of ALS, the protein TDP-43* does not function properly, disrupting the production of STMN2 and reducing its levels. Without sufficient STMN2, neurons may have a harder time repairing damage, which could contribute to disease progression.

STMN2 is already being targeted in clinical trials. QRL-201(by QurAlis), currently being evaluated in the ANQUR trial, is an antisense oligonucleotide (ASO) designed to restore STMN2 expression in people living with ALS. A Phase 3 trial is planned for 2027.

What did this study find?

In this new study, led by researchers at Harvard Medical School, statins increased STMN2 levels in cells where TDP-43 function was impaired. The researchers found that statins influenced a cellular process called the mevalonate pathway, activating a broader repair response involving a gene called ATF3. As a result, treated cells showed improved neurite growth, an early indicator of nerve repair.

How does this fit with previous research?

A previous study discovered a 28% reduced risk of developing ALS in people taking lovastatin, subsequently finding that lovastatin protected motor neurons and delayed disease progression in ALS mouse models. However, the connection between statin use and people living with ALS has been less clear, overall. Earlier safety reports raised concerns that statins might contribute to ALS risk or worsen disease, but subsequent research has generally not supported this association or, alternatively, showed a protective effect.

Most recently, a study by Canadian researchers at Sunnybrook Health Sciences Centre analyzed data from more than 3,400 participants in an ALS database and found no significant differences in survival or disease progression between people taking statins and those who were not. The findings suggested that statins neither improved nor worsened ALS outcomes.

The takeaway

While this research is still at an early stage and has not yet been peer reviewed, it identifies a potentially promising new way to boost STMN2 and support the natural repair mechanisms of motor neurons. At the same time, statins remain a complex area of ALS research, and more studies will be needed to determine whether these laboratory findings could eventually translate into benefits for people living with ALS.

* RNA is a group of molecules inside cells that help manage and carry out many of the cell’s activities. While some RNA molecules carry genetic instructions from DNA to help make proteins, others help control genes, regulate cellular processes, and keep the cell running smoothly.

Why are RNA “chaperones” important?

Certain short RNA* molecules can act as “chaperones” inside cells, helping proteins maintain their proper shape and function. Previous research showed that these RNA molecules can bind to TDP-43*, stabilizing the parts of the protein that normally interact with RNA and helping keep it in a healthy state. By maintaining the normal structure of TDP-43, RNA chaperones may help prevent the protein from misfolding and forming the aggregates commonly seen in ALS.

What did this study find?

In this study, researchers from University of Pennsylvania screened and engineered RNA chaperones that bind to regions of TDP-43. They identified two promising candidates, called Clip34 and Malat1_start, that helped stabilize TDP-43 and keep it in a healthy form. The team then further refined these molecules, creating enhanced RNA chaperones.

The researchers tested these RNA chaperones in several laboratory models, including motor neurons derived from cells donated by people living with ALS and a mouse model with TDP-43 pathology. The molecules reduced pathological TDP-43 aggregation while being small and targeted enough to preserve the protein’s normal function. By helping TDP-43 remain in its healthy state, the approach reduced toxic clumping without disrupting its essential role in the cell. In mice, treatment protected motor neurons and extended survival.

How does this fit with previous research?

Many therapeutic approaches explored for TDP-43 pathology aim to remove TDP-43 aggregates after they have already formed or reduce levels of abnormal TDP-43. This study takes the alternative approach by trying to prevent TDP-43 from becoming abnormal in the first place.

This strategy is important as it addresses two important problems at once: reducing the formation of TDP-43 clumps while also helping TDP-43 stay in the nucleus, where it performs many of its normal functions. Researchers still do not know whether ALS is driven more by the effects of TDP-43 aggregates, the loss of TDP-43’s normal activities, a combination of both, or even something else entirely. By targeting both processes at the same time, RNA chaperones offer a broader way to tackle TDP-43 pathology.

The takeaway

These findings point to a new direction for ALS research and drug development. Instead of focusing only on clearing protein aggregates after they form, this approach aims to prevent harmful aggregation in the first place by stabilizing TDP-43 early on and potentially keeping its function in cells. While much more research is needed before this could become a treatment for people living with ALS, the study suggests two new molecules to further explore.

ALS and frontotemporal dementia (FTD) can sometimes be caused by the same genetic variant, most commonly in a gene called C9orf72. This variant can lead to the buildup of toxic protein clumps inside motor neurons, known as dipeptide repeat proteins (DPRs). Over time, these harmful proteins are believed to interfere with normal cell function and contribute to the damage and death of neurons.

Why is cellular clean-up important?

Our cells have natural clearance systems that identify and remove damaged or unwanted proteins. In ALS, these systems can become overwhelmed or dysfunctional, allowing harmful proteins and clumps to accumulate. Researchers have therefore been exploring ways to strengthen these cellular clean-up pathways as a potential therapeutic strategy.

What did this study find?

In this study, researchers at the Università degli Studi di Milano investigated a protein called valosin-containing protein (VCP), which helps cells dispose of damaged proteins and maintain cellular health. They found that increasing VCP activity reduced the buildup of toxic DPRs and protected parts of the cell responsible for recycling waste (called lysosomes).

The researchers also tested SMER28, a compound that boosts cellular waste-clearing pathways. SMER28 reduced harmful protein accumulation in both laboratory cell models and motor neurons generated from cells donated by people living with C9-ALS. The treatment also improved several measures of normal cell function and supported healthier neuronal development.

The takeaway

More studies are needed to better understand how to translate these findings to a safe and effective therapeutic approach in humans. However, these findings suggest that helping cells better clear away harmful proteins and boosting VCP activity could be a strategy for ALS caused by the C9orf72 variant.

This news article highlights a new study by Northwestern University researchers, exploring how immune changes may contribute to disease. The immune system has long been shown to play a role in disease, but it is still unclear how and how it is linked to ALS progression.

Researchers analyzed blood and spinal cord samples from nearly 300 people with ALS and found that patterns of inflammation differed depending on the type of ALS (caused by the C9orf72 variant or not), how advanced the disease was, and how quickly it progressed.

They observed that immune cells involved in inflammation tended to gather around areas where motor neurons were being lost and where TDP-43 abnormalities were present. The findings suggest that damage inside motor neurons may trigger an immune response that can further contribute to disease progression.

Importantly, this does not mean inflammation causes ALS or determines when the disease begins. Instead, it suggests that inflammation may be one factor that could help explain why the disease progresses more quickly in some people than others.

The recently announced Longitude Prize on ALS marks a major global effort to accelerate the search for new treatments. This £7.5 million challenge brings together international, multidisciplinary teams to use artificial intelligence (AI) and large-scale patient data to identify and validate new drug targets for ALS.

In its first stage of competition, 20 teams from around the world have been awarded funding to begin this work. Next steps will progressively narrow the field in several steps, with those moving on receiving further rounds of support, leading up to a final prize for the most promising discovery.

We would like to congratulate a Canadian team, Espoir Biosciences, for being one of the groups awarded. This is a well-deserved recognition and it’s exciting to see progress and collaboration in this space.

We’re proud to have supported foundational work led by Dr. Alex Parker and his team that have led to the direction of Espoir Biosciences, and to see Canada highlighted on the global stage.

Further evidence darifenacin preserves nerve-muscle connections in ALS mouse models  

A new study from researchers supported at the Université de Montréal, led by Dr. Richard Robitaille, continued to explore whether supporting cells surrounding the neuromuscular junction (the connection between motor neurons and muscles) could help slow ALS progression. In an ALS mouse model, the researchers found that these support cells, called perisynaptic Schwann cells, become overactive and may lose their ability to help repair damaged nerve-muscle connections. Treatment with darifenacin, an already approved drug for overactive bladder symptoms, helped restore normal signaling in these models, preserving neuromuscular junctions, improving motor function, and reducing motor neuron loss.

Importantly, this evidence adds to the ongoing translational efforts led by Dr. Robitaille, whose team has already advanced darifenacin into clinical testing for ALS, including recruitment at Canadian sites. 

A new link between key ALS proteins

A new preprint study by a supported researcher at the University of Waterloo, led by Dr. Dale Martin, identified ZDHHC17 as a potential link between several neurodegenerative diseases, including ALS. ZDHHC17 helps carry out a cellular process called S-acylation, which acts like an address label for proteins, helping them get to the right place within cells.

The researchers found that ZDHHC17 interacts with several ALS-related proteins, including TDP-43, VCP, C9ORF72, FUS, and SQSTM1, and showed that disruptions in this pathway can alter protein localization and cellular health. Experiments in cell and fruit fly models suggested that loss of ZDHHC17 function can lead to motor impairments and increased toxicity. While the findings are still early and have not yet been peer reviewed, they point to a potentially shared biological pathway across multiple neurodegenerative diseases and highlight S-acylation as a new area for future ALS research.

New zebrafish C9-ALS model to identify and validate potential ALS therapies

A new study, led by Dr. Alex Parker at the CHUM Research Center (CRCHUM), developed and characterized a zebrafish model lacking the C9orf72 gene, using CRISPR/Cas9 technology. The research team found that these fish developed features relevant to ALS, including movement impairments and changes in nerve and muscle function. They then used the model to test compounds that had previously shown promise in a simpler roundworm (C. elegans) ALS model, helping determine whether the findings could be reproduced across different species.

Importantly, the study demonstrates the value of using multiple ALS models to identify and validate potential therapies before moving to more advanced preclinical testing. By showing that promising compounds can have beneficial effects across species, this work helps strengthen confidence in potential drug candidates and supports efforts to accelerate the development of new ALS treatments.