A new University of Toronto study has discovered a potential biomarker linked to the progression of multiple sclerosis (MS) that could help identify patients most likely to benefit from new drugs.
The findings were published today in Nature Immunology and validated in both mouse and human models.
We believe we have uncovered a potential biomarker that signals that a patient is experiencing so-called “compartmentalized inflammation” in the central nervous system, a phenomenon well-liked in the progression of MS. It was really hard to know who was progressing and who wasn’t.”
Jen Gommerman, professor and chair of immunology, U of T’s Temerty Faculty of Medicine
Canada has one of the highest rates of MS in the world with over 4,300 Canadians diagnosed with the condition each year, according to MS Canada.
About 10 percent of people with MS are initially diagnosed with progressive MS, which leads to gradually worsening symptoms and increasing disability over time. Patients initially diagnosed with relapsing-remitting multiple sclerosis, the most common form of the condition, can also go on to develop progressive multiple sclerosis.
“We have immunomodulatory drugs that can modulate the relapse and remission phase of the disease,” says Valeria Ramaglia, a scientist at University Health Network’s Krembil Brain Institute and assistant professor of immunology at Temerty Medicine.
“But for progressive MS, the landscape is completely different. We don’t have effective treatments.”
Ramaglia, who co-led the study with Gommerman, notes that until their study, the research field did not have a good model that replicated the pathology of progressive multiple sclerosis.
To understand the mechanisms driving progressive MS, researchers developed a new mouse model that mimics the damage to the brain’s gray matter seen in people with progressive MS. A hallmark of this so-called gray matter injury is compartmentalized inflammation in the leptomeninges, a thin, plastic-wrap-like membrane that surrounds the brain and spinal cord.
Using their mouse model, they also observed an approximately 800-fold increase in an immune signal called CXCL13 and significantly lower levels of another immune protein called BAFF.
By treating these mice with BTK inhibitor drugs—which are currently being tested in clinical trials to target progressive multiple sclerosis—the researchers mapped a circuit in the brain that led to gray matter injury and inflammation. They also found that BTK inhibitors restored CXCL13 and BAFF levels to those seen in healthy mice.
These results led the researchers to hypothesize that the ratio of CXCL13 to BAFF could be a surrogate marker for leptomeningeal inflammation.
To test the validity of their findings in humans, the researchers measured the CXCL13-to-BAFF ratio in postmortem brain tissues from people who had multiple sclerosis and in the cerebrospinal fluid of a living cohort of people with multiple sclerosis. In both cases, a high CXCL13-to-BAFF ratio was associated with greater compartmentalized inflammation in the brain.
So far, BTK inhibitors have seen mixed results in clinical trials in people with MS. Ramaglia says that without an easy way to detect leptomeningeal inflammation, the trials likely enrolled participants who did not have this trait and were unlikely to benefit from the drug. Any positive results from individuals with compartmentalized inflammation will then be diluted.
“If we can use the analogy as a surrogate to say which patients should be treated with a drug that targets leptomeningeal inflammation, that could revolutionize the way we do clinical trials and how we treat patients,” says Ramaglia.
As she builds her own research program at the Krembil Brain Institute, Ramaglia continues to work with Gommerman to explore how the CXCL13-to-BAFF ratio can be used to advance precision medicine for people with MS. They are working with the drug companies behind the BTK inhibitor trials to examine whether the participants who responded best to the drugs also had high CXCL13-to-BAFF ratios.
Ramaglia also plans to look at CXCL13 and BAFF levels in people with early MS to see if it can predict who is likely to develop progressive MS later.
She credits her time as a research associate in Gommerman’s lab with being instrumental in helping her become an independent researcher.
“Jen’s lab was a huge stepping stone for me. It gave me the space and independence to build my own research.”
This research was supported by the Canadian Institutes of Health Research, MS Canada, the National Multiple Sclerosis Society, and the United States Department of Defense.
