GlycoNet investigators identify a cancer-associated sugar as a new biomarker for scleroderma

 

A sugar that’s been linked to cancer could also serve as an early indicator of severe scleroderma, improving diagnosis and treatment options for patients with this rare disease.

 Posted: 29 February, 2024

 

GlycoNet investigators have discovered a new biomarker for scleroderma that could be used to predict who is at risk of severe disease progression, and potentially provide clues towards developing future treatments. 


Scleroderma, also called systemic sclerosis, is a rare autoimmune disease that affects an estimated 2.5 million people worldwide1. The disease is characterized by an overproduction of collagen and uncontrolled growth of skin cells, which results in hardening of the skin and internal organs. The thickening of connective tissue is called fibrosis, and in many cases, scleroderma can also damage internal organs such as the heart and lungs, which ultimately can cause death. 


“About 40 per cent of people with severe scleroderma die within five years of diagnosis” says co-principal investigator Dr. Lisa Willis, who is a glycoscientist and assistant professor at the University of Alberta. 


Although rare, the disease is quite devastating, impacting people in the prime of their life, with most people being diagnosed between 30 to 50 years of age. 


“My patients and their well-being are my primary motivation. As a clinician scientist, I am a clinician first. So I use research as a tool to solve the challenges faced by my patients,” says co-principal investigator Dr. Mo Osman, who is an immunologist and rheumatologist, as well as associate professor at the University of Alberta.


Although scleroderma is classified as an autoimmune disease, it is not often responsive to therapies that inhibit the immune system. No cure is available and treatment options are currently limited. Some patients undergo an expensive bone marrow transplant with varying levels of success and with many side effects. 


“What we want to be able to do is to figure out who is going to get the more severe form of the disease,” explains Dr. Willis. “Those are the people who may need a bone marrow transplantation early in the disease and need very close monitoring—because the earlier in the disease that you do the bone marrow transplantation, the more likely it is to be successful.”


When Dr. Osman met Dr. Willis in 2019, he was trying to decipher the similarities between scleroderma and aggressive cancers, as the relationship could hold clues to finding a biomarker and targeting the disease. Dr. Willis helped shift his quest for answers to glycomics—the study of sugars called glycans. 


“Lisa mentioned that she studies this glycan—polysialic acid—which I did not know anything about at that time,” says Dr. Osman. “She discussed how polysialic acid acts as an immune checkpoint.”


Polysialic acid is normally found on the surface of cells in the immune, nervous and reproductive systems, but it has also been known to be associated with metastatic cancer. As a result, Dr. Willis suspected that the glycan could also be playing a role in scleroderma.


In their recently published findings, the researchers found that polysialic acid was present in both the skin and blood of patients, with higher amounts found in instances of severe scleroderma. They also observed reduced levels of the glycan in patients who had received a bone marrow transplant, indicating that changes in polysialic acid are linked to disease progression.


The next phase of the research will help the research team further refine their findings by examining samples from patients who are in very early stages of the disease, to gather more data on how the level of polysialic acid early on correlates with eventual disease progression and severity. 


“We are hoping to develop a prognostic test for patients with systemic sclerosis and other autoimmune diseases,” says Dr. Osman. As a simple blood test, it would be non-invasive and inexpensive to implement with the technology already available in any clinical lab.


The research team is also working to decode the mechanism of scleroderma. 


“We do not have good evidence that the glycan is causing any of the pathogenesis of the disease, but we think based on some other research we’ve been doing that it might be,” says Dr. Willis. “And if that is the case, then intervening with the glycan’s functions would potentially allow us to treat the disease.” 


Studying rare diseases like scleroderma involves unique challenges that emphasize the importance of collaboration and dedicated research efforts. Due to low numbers of people with the disease, it can be difficult to access sufficient tissue samples. Another challenge in the case of scleroderma and other diseases where the immune system plays a role is that the human immune system is unique.


“Polysialic acid is really interesting because it doesn’t show up in mice the same way that it shows up in humans. So we might have found something that couldn’t have been found if we hadn’t been looking at human tissue,” explains Dr. Willis. “That’s one of the biggest challenges I think in scleroderma research—the lack of an animal model that captures human disease.”


“While they can be beneficial for developing a general understanding, these models certainly have major limitations related to understanding aspects related to therapies and prognosis in these diseases,” adds Dr. Osman. “Better understanding glycomics has certainly helped me better appreciate why.”


Glycomics as an emerging field is full of potential, driving the development of new diagnostics, tools and therapies. However, collaboration and funding remain essential to making these advancements possible. 


“We wouldn’t have gotten other grants without the preliminary data that GlycoNet enabled us to generate,” says Dr. Willis.


The team recently received a grant from the National Scleroderma Foundation. Their research was also recognized in the top 10 research advances of 2023 by Arthritis Society Canada.


“We’re both excited about making things better for patients and their families,” says Dr. Willis.


Both investigators also acknowledge their trainees for integral contributions to the research.


“The trainees are the ones who are troubleshooting. They’re the ones who are figuring out the best way to do the experiments,” says Dr. Willis. “The trainees have just been incredible on this project.” 


Support for the research and trainees was provided by GlycoNetScleroderma Canada, the Canadian Institutes of Health Research – Institute of Musculoskeletal Health and Arthritis, Natural Sciences and Engineering Research Council, Arthritis Society Canada, and the National Scleroderma Foundation.


1World Scleroderma Foundation

 
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