$300,000 awarded to Dr.Richard Robitaille, Université de Montréal, in collaboration with Dr. Danielle Arbour, Dr. Roberta Piovesana, Université de Montréal, and Dr. Robert Bowser, Barrow Neurological Institute
Biomarkers are biological measures that can be used to understand the real-time processes happening in the body. Validated biomarkers are urgently needed to help clinicians diagnose ALS, track progression of the disease and measure response to therapies. Dr. Robitaille and team believe that proteins related to the neuromuscular junction (NMJ) may help to fill this need.
The NMJ is the place where motor neurons connect to muscle fibers. This junction allows for signals from the brain to pass to muscles. Many researchers believe that one of the earliest events in ALS is the disconnection of motor neurons from muscles at the NMJ. As this disconnection occurs, NMJ-related proteins can be released into the bloodstream. With this grant, Dr. Robitaille will investigate whether any of these proteins could serve as a reliable biomarker for ALS.
Previous studies have revealed that some muscle types are more resistant to NMJ disconnection than others. For example, in both humans and ALS mouse models, the eye muscles preserve these connections longer, which is why many assistive devices for ALS use eye movements for control. By comparing resistant and vulnerable muscle types in a mouse model of ALS, Dr. Robitaille identified a set of candidate biomarkers reflective of NMJ dysfunction.
Here, the aim is to validate these candidate proteins as diagnostic and/or prognostic (progression) biomarkers using human fluid (plasma) samples. Additionally, the team will explore whether candidate biomarkers can be used to track treatment response in mice treated with an experimental therapy called darifenacin. Preclinical work showed that treatment with darifenacin slowed weight loss, maintained motor function, and increased life span in ALS mice, and as a result Dr. Robitaille recently received support through the ALS Association’s Clinical Trials Awards Program to move darifenacin into a human clinical trial in 2023.
Validation of these potential biomarkers could enhance diagnostic accuracy, lead to earlier diagnosis, and provide more accurate markers of ALS progression. Moreover, this work could help to confirm the target and selectivity of the experimental treatment darifenacin, which are important steps in the drug development pathway.