A recent study led by the University of Toronto has identified a potential biomarker that could be linked to the progression of multiple sclerosis (MS). The research, published in Nature Immunology, was validated using both mouse models and human samples.
Canada is among the countries with the highest rates of MS, with more than 4,300 new diagnoses each year, according to MS Canada. Approximately 10 percent of MS patients are initially diagnosed with progressive MS, which is characterized by a steady worsening of symptoms and increased disability. Many patients who start with relapsing-remitting MS may also develop progressive forms over time.
Valeria Ramaglia, a scientist at the University Health Network's Krembil Brain Institute and assistant professor at Temerty Medicine, explained: "We have immunomodulatory drugs that can modulate the relapsing and remitting phase of the disease. But for progressive MS, the landscape is completely different. We have no effective therapies."
Ramaglia co-led the study with Gommerman and noted that previous research lacked a suitable model for replicating progressive MS pathology. To address this gap, researchers developed a new mouse model reflecting grey matter damage seen in people with progressive MS. This type of injury is marked by inflammation within the leptomeninges—a membrane surrounding the brain and spinal cord.
The team observed an approximately 800-fold increase in CXCL13, an immune signal, alongside much lower levels of another protein called BAFF in their mouse model. Treatment with BTK inhibitor drugs—currently being tested in clinical trials—restored these immune markers to normal levels in mice.
These findings led researchers to propose that the ratio between CXCL13 and BAFF could serve as a marker for leptomeningeal inflammation. They tested this hypothesis by measuring this ratio in postmortem brain tissue from people who had MS and in cerebrospinal fluid from living patients. In both cases, higher ratios were linked to greater compartmentalized inflammation.
BTK inhibitors have shown mixed results so far in clinical trials involving people with MS. Ramaglia suggested that without reliable ways to detect leptomeningeal inflammation, some trial participants may not have had this feature and thus would not benefit from such treatments: "If we can use the ratio as a proxy to tell which patients should be treated with a drug that targets leptomeningeal inflammation, that can revolutionize the way we do clinical trials and how we treat patients," she said.
Ramaglia continues her research at Krembil Brain Institute while collaborating on further studies into how this biomarker could support precision medicine approaches for MS treatment. The team is working with pharmaceutical companies running BTK inhibitor trials to determine if those who responded best had high CXCL13-to-BAFF ratios.
She also plans to investigate whether these immune markers might predict which individuals with early-stage MS are likely to progress toward more severe forms.
Reflecting on her career development, Ramaglia stated: "Jen's lab was a huge stepping stone for me. She gave me the space and independence to build my own research."
This study received funding from organizations including the Canadian Institutes of Health Research, MS Canada, National Multiple Sclerosis Society, and United States Department of Defense.
