Moving the Needle Against ALS

Chantelle Sephton, PhD – Career Transition Award, ALS Canada-Brain Canada Discovery Grant and Future Leaders in Canadian Brain Research recipient

THE ENERGY CRISIS IN ALS

Chantelle Sephton, PhD and colleagues showed that nerve cells affected by ALS accumulate toxic fats, which damages cells and contributes to progression of the disease. Using laboratory models and human tissue, her research identified why – ALS disrupts the way nerve cells metabolize fats, causing energy production to fail and harmful fats to build up inside cells. They then identified what to do about it; the team showed that a drug called arimoclomol could restore the fat metabolism process, reducing the buildup of toxic lipids and improving nerve cell health. Prof. Sephton’s work reveals a whole new biological pathway involved in ALS and highlights a promising therapeutic target for slowing neurodegeneration.

Janice Robertson, PhD – Arthur J. Hudson Translational Team Grant and ALS Canada-Brain Canada Discovery Grant recipient

CONNECTING THE DOTS

Janice Robertson, PhD and team helped reveal precisely how the most common genetic cause of ALS damages the brain and nervous system. Her research showed that when a gene called C9orf72 malfunctions, this worsens the buildup of the toxic TDP-43 protein. This is a hallmark of ALS – more TDP-43 buildup means accelerated damage to nerve cells. By developing important new mouse models of the disease, Prof. Robertson’s work gave researchers valuable tools to study how C9orf72 affects cells in ALS and opened new avenues for developing treatments targeting this genetic malfunction.

Prof. Robertson’s finding has been cited in more than a dozen patents, including research methods and tools, diagnostics, and a clinical trial testing whether metformin, the drug commonly prescribed for diabetes, can reduce harmful proteins created by the malfunctioning C9orf72.

Éric Lécuyer, PhD – ALS Canada-Brain Canada Discovery Grant recipient

CELLS UNDER STRESS

Éric Lécuyer, PhD and colleagues helped uncover a critical factor driving nerve cell damage in ALS – tiny clusters of proteins and genetic material that form when cells are under stress. Their research showed that these clusters do not behave normally in ALS and contribute to the death of nerve cells. By identifying hundreds of previously unknown components involved in this process, Prof. Lécuyer’s work highlighted promising new targets for future treatments aimed at slowing or preventing nerve cell damage.

Prof. Lecuyer’s publication has been cited over 900 times in follow-on discoveries by other research teams, as well as in seven patents, including a method to inhibit the formation of stress granules and treat ALS.

Véronique Bélzil, PhD – Career Transition Award recipient

COMMON ROOTS OF ALS

Véronique Bélzil, PhD and team discovered that inherited and non-inherited forms of ALS share many of the same underlying biological changes. By identifying new genes and pathways involved in the disease, including the promising target SERPINA1, their work is uncovering common drivers of ALS and opening new avenues for treatment development that will benefit a broad range of people living with the disease.

Jean-Pierre Julien, PhD – Arthur J. Hudson Translational Team Grant recipient

THE INFLAMMATION CONNECTION

Jean-Pierre Julien, PhD and colleagues uncovered a critical connection between two major drivers of ALS: TDP-43, the toxic protein found in most cases of the disease, and inflammation. Their research showed that these processes fuel one another, accelerating damage to nerve cells – and that calming the inflammatory response could slow disease progression. In animal studies, treatments targeting this pathway delayed the course of ALS, opening a promising new therapeutic avenue that has since led to compounds derived from Ashwagandha advancing into Phase 2 clinical trials.

Dr. Angela Genge – ALS Canada-Brain Canada Discovery Grant recipient

RESTORING THE CONTROL SYSTEM

Dr. Angela Genge and colleagues conducted the first clinical trial to test whether microRNAs, which are decreased in ALS, can be restored. MicroRNAs act as dimmer switches that turn genes on and off and maintain healthy cell function. The team administered a drug called enoxacin to ALS patients and what they found was encouraging – the drug increased microRNA levels in both their blood and spinal fluid, without causing serious side effects. These findings provide early evidence that targeting this pathway may be a promising new treatment strategy and support further clinical trials to determine whether it can slow disease progression.

Alex Parker, PhD – ALS Canada-Brain Canada Discovery Grant recipient

PROBIOTICS AS TREATMENT

Alex Parker, PhD and team discovered that a specific probiotic strain called HA-114 protects motor neurons, which progressively degenerate in ALS, by restoring impaired lipid metabolism and rebalancing mitochondrial energy. This restorative effect, which the team proved in worm and mouse models, catalyzed additional investment to support a human clinical trial involving 100 participants. This high-impact work offers a promising, low-side-effect avenue for treating ALS.