Is there a link between metabolism and ALS disease progression?

Investigating the hormone leptin as a possible new ALS biomarker thanks to a Discovery Grant

“In our project, there is a crucial collaboration between clinical and foundational research.” – Dr. Jasna Kriz

While a fast metabolism is often thought of as an asset, there is increasing evidence that in ALS patients, hypermetabolism could be linked to faster-progressing disease. Now, with funding from the ALS Society of Canada and Brain Canada, a team made up of Dr. Jasna Kriz (CERVO Brain Research Centre, Université Laval), Dr. Nicolas Dupré (CHU de Québec-Université Laval), and Dr. Angela Genge (The Neuro – Montreal Neurological Institute-Hospital) will explore whether leptin, a hormone released from the fat cells located in adipose tissues, could be a helpful marker to determine whether a person with ALS will be a fast or slow progressor – and whether targeting and regulating leptin could one day inform viable therapies for ALS.

HELPING ANSWER PATIENTS’ MOST PRESSING QUESTION

An ALS diagnosis raises many uncertainties for patients and their families; often, the most urgent question is how quickly the disease will advance. A major benefit of this project, the researchers explain, is that it explores an aspect of ALS that is both scientifically significant, and intimately meaningful to the people whose lives are most affected.

“The question this project aims to answer is one that my patients ask all the time,” says Dupré, who is director of the ALS clinic at the CHU de Québec-Université Laval. “Just this morning, I had ALS patients who were asking me, ‘Am I progressing quickly or slowly?’”

The new stage of the project will bring clinicians closer to answering this important question with confidence. As Dupré explains, patients who present as slow progressors could find some comfort in this knowledge, while fast progressors could be more easily identified for clinical trials.

HOW METABOLIC IMBALANCE LINKS TO FASTER ALS PROGRESSION

Kriz explains that ALS is a highly heterogeneous disease – meaning that each person’s journey with ALS will be different. Its underlying causes, presentation, and prognosis for patients vary widely; while some individuals may live with ALS for decades, others decline rapidly. According to Kriz, about 10-20% of patients fall into the “fast progressor” category.

“From a scientific point of view, this heterogeneity makes ALS a very challenging disease,” she says. “In our previous work, we wanted to see whether patients with slow or fast progressing disease had different immune markers, and determine whether we could find a link between these differences and their disease progression.” After studying blood plasma samples from people who had more rapidly progressing ALS, Kriz discovered that fast progressors often showed decreased levels of leptin, and increased levels of specific immune markers called CCL16 and sTNF-RII.

The next step: with funding in hand, Kriz, Dupré and Genge will examine a larger, more diverse variety of samples to confirm whether these specific blood markers are directly linked to more aggressive forms of ALS, and whether they might serve as predictors of disease progression. Using cell and mouse models, they will also investigate whether manipulating the markers could influence the progression of ALS, and whether the mechanism behind reduced leptin levels could inform future therapeutic strategies. Their hope is that by restoring balance to metabolic markers like leptin – known as achieving metabolic homeostasis – fast progressors could potentially become slow progressors.

HOW A NEW BIOMARKER COULD CHANGE THE GAME

Biomarkers, including blood counts and cholesterol levels, are indicators in the body that can be used as benchmarks during the diagnosis of diseases, and then monitored to gauge how well a treatment is working. Dr. Genge, director of the ALS clinic and the Clinical Research Unit at The Neuro, says the possibility of leptin levels becoming a new biomarker for ALS is an exciting prospect.

“What Jasna is exploring with leptin is a really strong opportunity to have a biomarker that we can use in real time,” Genge enthuses. “Using something as simple as a blood test, we could determine if a drug is having a positive effect.”

She notes that a lack of biomarkers for ALS creates challenges at the clinical level and having this time of biomarker could drastically improve clinical trials in ALS. Positive outcomes depend on the ability to determine quickly whether a treatment is having the desired effect; no physician wants to wait and see whether their patient suffers a decline. By contrast, accurate and accessible biomarkers are quick to show “that they’re betting on a winner,” as Genge puts it.

The promise extends into ALS therapies, she says: “In turn, this could help streamline ALS drug development, and help us be able to develop more effective treatments, faster.”

RESEARCH THAT BUILDS COLLABORATION – AND THE NEXT GENERATION

In describing the funded partnership, Kriz quickly points to the benefit of multiple perspectives: “In our project, there is a crucial collaboration between clinical and foundational research.” Dupré echoes the sentiment: “Often, the best scientific opportunities occur when you combine an expert clinician in the given disease, with an expert scientist,” he says. “And that’s the spirit in which Jasna and I have been collaborating for the past decade.”

Kriz and Dupré first met while completing their postdoctoral work at the Montreal General Hospital. As they advanced in their careers, they have seen the impact of funding on how the field develops, especially for the new generation of promising researchers. Both explain that this current project is largely indebted to the work of a very talented resident, Dr. Vincent Picher-Martel, who first instigated the endeavour in collaboration with Dupré.

“This seed money allows us to develop novel ideas, and also creates opportunities for training,” explains Dupré. “This has been a successful project, and it has nurtured the future of ALS research in Canada, because we are able to engage the best students, and they become interested in this disease.”

“And for these new researchers, it’s really a passion,” he adds. “They meet the patients, they meet the scientists, and they develop skills that will ensure a successful career in this field.”

Funding that makes a difference

The Discovery Grant Program makes these connections possible with a funding model that favours interdisciplinary collaboration, bringing the best minds together to tackle complex problems.Discovery Grants give promising novel ideas the fuel they need to gain traction; in 2021, up to eight projects will benefit from $1M in total funding.

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $23 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease.

The Discovery Grant Program has been made possible by Brain Canada, through the Canada Brain Research Fund (with financial support from Health Canada) and the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.