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Is it possible to target the root cause of ALS linked to the C9ORF72 gene?

Dr. Christopher E. Pearson (left) and Dr. Ekaterina Rogaeva

Controlling a DNA repeat expansion may indicate a path for future treatment

“The best thing about being a scientist in this field is the people we work with, and the families we work for.” – Dr. Christopher E. Pearson.

Dr. Christopher E. Pearson, a genetics expert based at The Hospital for Sick Children (SickKids) in Toronto and Full-Professor at the University of Toronto, has studied DNA repeat expansions, a type of genetic mutation common to neurodegenerative disease, for decades. Recently, his team successfully reversed one version of this type of mutation in a Huntington’s disease animal model, a discovery that may have significant implications for a specific form of ALS.

Now, thanks to funding from the ALS Society of Canada and Brain Canada, Pearson is teaming up with Dr. Ekaterina Rogaeva, a geneticist at the Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto, and extending this research by focusing on ALS mouse models. Their goal: to understand the relationship between elements that affect how a problematic repeat expansion of the  C9orf72 gene in a subset of ALS cases could be shortened – and whether a known anti-cancer drug, fluorodeoxyuridine (FUdR), could affect this genetic mutation in an ALS mouse model, indicating a potential therapeutic approach.

Exploring DNA repeat expansions – mice, cats and fat, fat rats

Both Pearson and Rogaeva have extensive experience working with diseases that involve a type of genetic mutation called repeat expansion, among them Huntington’s, frontotemporal dementia (FTD), and ALS. But what is a repeat expansion? Pearson puts it like this: “Imagine the genome written out in three-letter words, where a gene would be coherent sentences; a standard mutation could cause a ‘spelling mistake’, but a repeat expansion would cause words to reiterate.”

“If the healthy gene sequence was a simple sentence – ‘the cat ate the fat rat’ – a basic mutation might produce ‘the gat ate the fat rat’,” he continues. “But with a repeat expansion, we see it stretch out as ‘the cat ate the fat fat fat fat rat.’” In these mutations, a section of DNA can be abnormally repeated hundreds or even thousands of times – eventually contributing to disease onset in some people.

Pearson explains that the ultimate goal of his work with Dr. Rogaeva is to understand how to stop the mutation in ALS, and ideally, reverse it.

“Understanding this type of mutation has been the focus of my career for over 25 years,” Pearson says. “This particular repeat is very challenging. It’s not a very well-behaved sequence; it’s hard to understand how it transmits this way, and continues to expand in the tissues.”

“But Dr. Rogaeva and I, and our labs, we’re actually driven on by that difficulty,” he adds. “I think that’s why we’re a good team.”

Never losing sight of ALS patients and their families

In addition to the project’s use of mice, Pearson emphasizes that the team will also be working with patient-derived cell lines. “We don’t want to get lost in the model, and lose sight of the human beings affected by ALS” he says. “We’re aware that we need to check that the model accurately reflects how the disease operates in humans.”

Why is this so important? He explains, “The best thing about being a scientist in this field is the people we work with, and the families we work for.”

“As researchers, we could make a discovery today that will change all of our tomorrows,” he says. “But it really comes down to the people.”

Chromatin and cell metabolism: What’s in your suitcase?

With their funding, Drs. Pearson and Rogaeva will focus on how the C9ORF72 repeat makes an impact on epigenetics, which are modifications to the DNA structure as opposed to its code. They are specifically interested in two aspects called chromatin structure and CpG DNA methylation. Preliminary work by Pearson has already demonstrated that the C9ORF72 expansion mutation causes a defect in chromatin structure, particularly something called chromatin compaction, but the cause of this has not yet been discovered.

“We’re looking at how the chromatin gets packaged, because essentially, the way a gene is packaged determines how it functions,” Pearson says. “It’s a bit like packing for a vacation, where the gear you bring determines what activities you will do: sturdy boots for a day of hiking versus a swimsuit for a day at the beach.”

In past research, the team has learned that the chromatin packaging is sensitive both to the repeat expansion size and to modifications on the DNA itself. Dr. Rogaeva has shown that chemically modified elements of the repeat expansion, particularly a modification called DNA methylation, can change the way the gene is packaged, and thus how it will operate.

The team’s preliminary data drew on their earlier work, showing that administering FUdR to cells influences how the chromatin is packaged – essentially repacking the suitcase, and thus changing the itinerary of the trip in a positive way. “When we put a drug on the cells, we changed the chromatin compaction, and it was really exciting as experimentalists to see that we could have this effect,” says Pearson.

With their new funding, the team will work to further determine the interrelationship of methylation, chromatin compaction, and how these connect to the repeat expansion of C9ORF72. Part of their effort will also be to test whether FUdR might be effective in reducing the problematic ALS-causing C9orf72 expansion, as a different substance did in Pearson’s Huntington’s research. All of this work is done with a mind to find novel ways of treating people with ALS caused by C9ORF72 mutation.

Long-awaited partnership is “a very complementary three-legged race”

In geometry, parallel paths never meet – but in research, sometimes they do. Drs. Pearson and Rogaeva graduated within a few years of each other, both began working on aspects of repeat expansion diseases, and both are now professors at the University of Toronto. Yet this project is their first-ever collaboration.

“We’ve always wanted to work together, but there’s never been a project that matched as perfectly as this one does,” Pearson explains. “Each of us looks at the other’s research and says, ‘wow, what you’re doing is very complicated and exciting,’” he laughs. “We work on the same problems, but in very different ways, and we realized we should combine those strengths – it’s become a very complementary three-legged race, that we are lucky to run together.”

Dr. David Taylor, Vice President of Research for the ALS Society of Canada, agrees that theirs is a promising pairing: “Dr. Pearson and Dr. Rogaeva work on very complementary avenues of ALS research and with this funding they can finally collaborate in a powerful way. Together I expect they will bring key advancements to our understanding of C9ORF72 and our ability to treat ALS caused by its mutation.”

“The Discovery Grants Program creates opportunities for unique multidisciplinary teams to ask innovative questions,” says Dr. Viviane Poupon, President and CEO of Brain Canada. “We envision a future without ALS, and we believe that collaboration is the best way to get there.

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. A key component of the ALS Canada Research Program, 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.

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