“We would like to bring hope to ALS patients. Our final goal is to find something that could really help alleviate the symptoms in ALS patients. That’s a long-term goal, but this study might be a first step to a novel therapeutic approach.” – Dr. Hoon-Ki Sung

Two of the prominent hallmarks of ALS are weight loss and metabolic dysfunction. There are clues that hypermetabolism – when the body uses too much energy to regulate things like appetite, temperature, and hormones – might be a contributing factor, but there hasn’t been an effective way to study these questions.

Until now.

Using a new mouse model, Dr. Jeehye Park, a geneticist and molecular biologist at The Hospital for Sick Children (SickKids), is teaming up with experts in metabolism in hope of understanding how and why ALS patients lose weight. The answers may provide crucial insights into novel ways to slow down disease progression and improve quality of life for people with ALS.

A new way to look at metabolism in ALS

The exceptional new tool used in the study was actually created by Dr. Park’s laboratory: a “knock-in mouse model” of MATR3 dysfunction, one of the lesser understood genetic causes of ALS.

Knock-in mouse models are often considered to be more clinically relevant because they express the mutant protein at normal levels, unlike other types of models which overexpress the protein. Without the right levels, it can be difficult to tell if the research findings are linked to a disease or simply due to the presence of too much protein.

Dr. Park created the innovative new model with funding from an ALS Canada-Brain Canada Career Transition Award in 2016 and a 2019 ALS Canada Project Grant. Now, this year’s Discovery Grant is allowing her to use her model to ask new questions, specifically about metabolism.

Soon after the model was created, Dr. Park noticed something interesting in her mice. With just one genetic change, they began to develop all the hallmarks of ALS: motor neuron defects, muscle weakness, and crucially for this study, weight loss.

That’s when Dr. Hoon-Ki Sung, who specializes in studying metabolic processes at SickKids, comes into the picture.

“It felt like destiny”

Though they work on two very different physiological processes in two separate labs, Dr. Park and Dr. Sung were already friends. They both hail from South Korea, and would grab lunch together to talk about their research.

“Dr. Sung is a senior researcher to me, so I learn a lot from him, and not just about research,” said Dr. Park.

Once Dr. Park told Dr. Sung that her mice weren’t keeping weight on, his interest was piqued. Metabolism is his specialty.

“It felt like destiny that our research would come together,” said Dr. Sung.

Though not an ALS specialist, he knew there was a recent research suggestion that the hypothalamus, which governs our metabolic processes, might be compromised in ALS.

But it is yet unknown whether hypermetabolism contributes to the progression of ALS in patients, or what the hypothalamus’ role might be. It has so far been an unopened door.

Dr. Park’s MATR3 mouse model might be the key that opens it.

Dr. Park and Dr. Sung hope their research can illuminate some of the early processes happening in ALS patients with a MATR3 mutation, allowing for earlier intervention. It might also open the door to new therapies, including non-invasive ones to mitigate hypermetabolism, like diet and environmental interventions that help patients keep weight on and possibly slow the progression of the disease. Finally, it will help us understand the potential role of the hypothalamus in ALS, something that hasn’t really been explored before.

“This study was ranked very high for the novelty factor,” said Dr. David Taylor, Vice President of Research for the ALS Society of Canada. “It’s a really unique one. They are giving us the ability to look at something that’s definitely happening in humans, in a way it hasn’t previously been examined.”

There from the beginning

Dr. Park started at SickKids six years ago. As a new principal investigator, she chose to focus on ALS because there is so much left that needs to be explored. “I wanted to try to contribute to something where I could do my best,” she said.

She’s already made a significant contribution to the field with her new mouse model, which was published in Nature Communications in 2020.

“I’ve been fortunate to receive so much support from ALS Canada and Brain Canada,” she said. “Few agencies like to fund something so preliminary that has not been done before. But with their support, I’ve been able to come this far.”

“It really is a remarkable model,” Dr. Sung confirms. Beyond their studies on metabolism and the hypothalamus, the model will be available to ALS researchers more broadly, who can work to illuminate other aspects of this understudied cause of ALS.

Funding that makes an impact

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $24 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. In 2022, nine projects awarded through the 2021 Discovery Grant Program will benefit from $1.125 million in funding.

“This partnership allows researchers to collaborate on leading-edge projects and, ultimately, have a positive impact on those living with ALS,” says Dr. Catherine Ferland, Chief Research and Program Officer at Brain Canada.

The Discovery Grant Program has been made possible with the financial support of Health Canada, through the Canada Brain Research Fund, an innovative arrangement between the Government of Canada (through Health Canada) and Brain Canada Foundation, and of 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.