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A novel collaboration brings decades of expertise to ALS research

The ALS Canada-Brain Canada Discovery Grant enables combined research into Simoa immunoassays based on functioning of the Sod1 gene.

“This new technology will help us establish and detect biomarkers. Because of this grant funding, we can test our new ideas – ideas we have developed together based on both of our individual experiences.”  – Dr. Gerhard Multhaup

Dr. Angela Genge has been working on clinical trials for ALS for years, but there’s still a major hurdle to identifying effective treatments.

“We’re still using functional measures to see whether or not something is working,” she said.  This includes more subjective measures such as patient self-reporting or observations by clinicians, which she says, is not the best.

Dr. Genge has a clear call for what’s needed: “We need to bring in people who are working on biomarkers in the neurodegenerative space and get their expertise in biomarker development focused on ALS.”

That’s where Dr. Gerhard Multhaup comes in. Dr. Multhaup is in the Pharmacology Department at McGill University and he specializes in molecular causes of Alzheimer’s disease, a field that has a much larger body of biomarker work than ALS.

After Dr. Genge gave a guest presentation about ALS in a class Dr. Multhaup was teaching on neurodegenerative diseases, they began to talk about collaborating. How could Dr. Multhaup bring together his experience in biomarker development with Dr. Genge’s experience in clinical trials? The answer came with a gene called SOD1 – and with help from an ALS Canada-Brain Canada Discovery Grant.

A gene with a history

SOD1 was the very first gene identified as a causal factor in ALS, and it contributes to 2-3% of cases. SOD1’s day job is to bind to copper and zinc as co-factors, creating a protein whose function is to break down toxic oxygen molecules in our bodies, making it an “antioxidant.” But when the gene mutates, it can cause a protein to misfold (i.e. change from its standard shape in a way that can cause it to malfunction) and gain a toxic function within motor neurons.

The presence of misfolded protein is bad news. There’s a silver lining though: it could also serve as a biomarker, the crucial piece missing in many ALS clinical trials. What if we could track the physical states SOD1 goes through as it misfolds to tell us how the disease is progressing?

“That is the reason why we are grateful for the Discovery Grant,” Dr. Multhaup said. “Now we can test these ideas to find new biomarkers.”

“What’s going on with misfolded SOD1 is a gap of knowledge,” Dr. Multhaup said. “With technology and with our different backgrounds, we want to fill this gap.”

New tech that does the “unthinkable”

The technology Dr. Multhaup is referring to is single molecule array (Simoa) immunoassays, which can give us an impressively clear picture of proteins in biofluids. In addition to being highly sensitive, it can test biofluids that are easier to draw from patients, like blood, as opposed to something like cerebrospinal fluid, which can be more invasive to collect.

“Why is this an exciting time? Because we have all this new technology!” said Dr. Multhaup. “It was unthinkable to quantify those misfolded proteins in serum or blood even 10 or 15 years ago.”

“These cool technologies are allowing us to get closer to the disease itself,” he continued. “We can observe things like misfolded proteins and understand the structures and mechanisms of abnormal and normal fibers. That’s why investment in core facilities and equipment is so important for basic researchers, like me, but also for clinicians.”

More crosstalk = more answers

SOD1 has been studied in relation to ALS, Alzheimer’s disease and other neurodegenerative diseases for decades, including by Dr. Multhaup, who has specialized in metal-binding proteins since he started as a researcher in Germany nearly 30 years ago.

“Through advances in research and technology, we now understand that the brain is a single, complex, and integrated system with commonalities across disorders,” explains Dr. Catherine Ferland, Chief Research and Programs Officer at Brain Canada. “This collaboration is a great example of how widening the scope of inquiry and broadening perspectives can lead to insightful discoveries.”

However, according to Dr. Genge, this kind of collaboration between different disease specialists is rare.

“It’s pretty special that we’re working together,” she said. She noted how ALS, as a relatively small field when it comes to funding and researchers, can benefit greatly from the work going on by other neurodegenerative disease researchers. Her hope is to encourage more scientists with skills and knowledge in identifying biomarkers to contribute their abilities to ALS research, like Dr. Multhaup has.

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.

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, 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.

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