Could inflammation in this pathway provide a new target for ALS therapies?

Discovery Grant empowers Canadian team to examine the cGAS-STING pathway across a range of ALS models

“The Discovery Grant is very crucial for us,” says Dr. Luo, “since it allows us to quickly look at the outcome.” Dr. Cashman also emphasizes speed as a bonus of this model of funding: “It enables teams like ours to do a short-term, relatively inexpensive study to hopefully implicate a new target for translation and more mechanistic work, which might then be funded by a larger grant, for a longer-term project.”

A newly identified pathway has been piquing research interest around the world for its possible role in ALS. Recently, Canadian virologist Dr. Honglin Luo, in collaboration with her colleague Dr. Neil Cashman, discovered that an immune pathway known as cGAS-STING – a catchier abbreviation for cyclic GMP-AMP synthase-stimulator of interferon genes – is activated by mutations in the SOD1 gene, which is a causal factor of ALS.

Now, with the support of a 2020 Discovery Grant, the University of British Columbia-based team will push further in determining the role cGAS-STING plays in ALS, and whether this pathway could be a viable target for future treatment.

Three countries, one common pathway

In August of 2020, an American study published in Nature linked C9ORF72 ALS to inflammation mediated by the cGAS-STING pathway; very shortly after, in October, an Australian paper in Cell linked cGAS-STING activation to TDP-43 (an ALS-linked protein encoded in the TARDP gene). Dr. Luo’s discovery looped in SOD1, adding further evidence that neuroinflammation triggered by cGAS-STING could be a shared feature across different presentations of ALS.

For context: neuroinflammation is common to several neurodegenerative diseases and likely plays a pivotal role in disease progression. In ALS, neuroinflammation seems to be linked to an abnormal activation of a person’s innate immune response; for the cGAS-STING pathway, this can be sparked by the presence of wayward cytosolic DNA resulting from a genetic mutation. Together, these three studies may suggest that blocking this pathway could be a viable therapeutic option for ALS to be tested in future clinical trials.

Discovery Grant powers up the project

Now, supported by this funding, Drs. Luo and Cashman will accelerate their work. The next step? Seeing whether genetically or pharmaceutically suppressing cGAS-STING might alter the course of disease in an ALS model mouse, to see whether this would be an effective target for treatment. Intriguingly, Dr. Luo has observed cGAS-STING activation very early in these mice, so blocking the pathway may delay disease onset and/or slow disease progression.

Dr. David Taylor, Vice President of Research for the ALS Society of Canada, explains that the project is particularly exciting because while many different genes cause ALS, these discoveries could point to a communal process that is widely shared. “The more independently verified evidence we have around therapeutic targets, the more confidence there is going into the clinical trial stage,” says Taylor.

Two ambitious experiments – and how “knockout” mice can help

What comes next: the team will continue their work with a dual experiment, with part one being focused on studying SOD1 ALS in mouse models. Critically, some mice will have the cGAS-STING pathway suppressed, or “knocked out,” in order to see whether deactivating this critical pathway delays the disease. All the mice will then undergo a variety of tests – monitoring their motor skills and grip strength, among other indicators – to see whether removing cGAS-STING from the equation leads to delayed progression of ALS symptoms. Researchers will be watching to see whether the control group of SOD1 mice develop neuroinflammation resulting from activation of the cGAS-STING pathway, and whether the knockout mice do not.

Dr. Luo explains that in a parallel experiment, they will also look at cGAS-STING suppression in vitro, using cell cultures, as a means of quickly assessing the role in a variety of other ALS types, and extending the scope of the study beyond SOD1. Her team hopes to confirm that supressing cGAS-STING protects against the cellular harm caused by multiple types of ALS triggers: “I hope we can identify this as a therapeutic target to limit the progression of the disease,” she says.

Supporting bold partnerships for a hopeful future

The grant will take Drs. Luo and Cashman’s collaboration to a new level. “The Discovery Grant is very crucial for us,” says Dr. Luo, “since it allows us to quickly look at the outcome.” Dr. Cashman also emphasizes speed as a bonus of this model of funding: “It enables teams like ours to do a short-term, relatively inexpensive study to hopefully implicate a new target for translation and more mechanistic work, which might then be funded by a larger grant, for a longer-term project.”

This is not the first time the two have worked together. Fascinated by virus-host interactions, Dr. Luo had previously focused on conditions including myocarditis and lung cancer. But when her work began to intersect with ALS roughly five years ago, she reached out to fellow UBC researcher Dr. Cashman for his input. “It has been an absolute pleasure and an honor to help a younger scientist achieve what she wanted to accomplish,” recalls Dr. Cashman, a career ALS clinician-scientist with 35 years’ experience to his name. They have been connected ever since, as Dr. Luo’s work in the field has grown.

Dr. Cashman says things have changed immensely over the decades he has devoted to ALS care and research: “Back in the old days, we would make the diagnosis and kind of hold the hands of the patients and their families. There was only symptomatic therapy, and there was no understanding of the genetics of ALS.” All that has improved over the ensuing decades, he says, from the emergence of the first drug therapies in the 1990s to today’s growing understanding of the complex but interacting genetics of ALS.

His perspective? “It’s gone from being a hopeless disease, to becoming a hopeful one,” he says. “There’s never been a time in history where more people are working on and thinking about ALS.”

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, 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 the study of the disease. The Discovery Grant Program is designed to fuel the innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve the quality of life for people and families affected by this devastating disease.

“The Discovery Grant Program helps bring together unique teams, encouraging researchers to combine their expertise in novel ways,” said Dr. Viviane Poupon, President and CEO of Brain Canada. “We are thrilled to partner with the ALS Society of Canada to fund research, accelerate breakthroughs and help improve outcomes for Canadians with ALS.”

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.