ACTRIMS 2026: Blocking C3 protein seen to ease MS severity in older mice
Targeting C3 protein could be a potential treatment strategy
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Blocking a complement protein called C3 reduced disease severity in older mice but not in younger ones, the researchers saw in using a mouse model designed to mimic progressive disease. (Photo from iStock)
- Age is a key risk factor for multiple sclerosis (MS) progression, but it is not fully understood why.
- A mouse study showed that complement activity might play a key role in age-related MS progression.
- Blocking C3 protein reduced disease severity in older mice, suggesting a potential progressive MS treatment.
The complement system — part of the immune system that helps defend against infections — may play a key role in age-related disease progression in multiple sclerosis (MS), according to findings from a mouse study.
In fact, blocking a complement protein called C3 reduced disease severity in older mice but not in younger ones, the researchers saw in using a mouse model designed to mimic progressive disease.
“We found that inhibition of C3 activation in aged but not young mice resulted in milder disease,” the team wrote in a study abstract.
Valeria Ramaglia, PhD, a professor of immunology at the University of Toronto, presented these findings at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, held last week in California and virtually. The talk was titled “Complement as Driver of Age-dependent Progression: Insights from a Mouse Model and MS.”
New research is now underway to determine whether targeting the C3 protein could be a potential treatment strategy in MS.
Age is one of the main risk factors for disability progression in MS, but the biological processes behind this are not fully understood.
Researchers suspect that inflammation in the leptomeninges — membranes that surround the brain and spinal cord — may drive this progression. Immune cells have been shown to form clusters in those membranes and release harmful molecules into the spinal fluid that damage nearby brain tissue.
One vulnerable structure is the hippocampus, which plays a role in learning and memory and sits close to both the leptomeninges and spinal fluid-filled brain cavities.
Researchers create model to studying disease processes
To study how age affects these processes, the team created a mouse model that recapitulated leptomeningeal inflammation, with animals showing clusters of immune cells in these membranes. The model was created by transferring inflammatory immune cells primed to cause progressive MS from donor mice into healthy mice.
The researchers transferred the immune cells into animals of different ages, and found that age clearly determined the course of the disease.
“If we transfer … cells into young mice, the mice get sick, but they recover. But if we transfer them into aged mice, they get sick and they stay sick,” Ramaglia said.
Additionally, the older mice showed persistent signs of inflammation in the leptomeninges and significant damage in the hippocampus relative to healthy animals. In the young mice, these features resolved.
To understand what could be causing the differences between aged and young mice, the team examined the protein composition of the spinal fluid.
According to the researchers, complement activation emerged as the strongest age-related signal. Additional analyses showed that the complement protein C3 was produced in the leptomeninges of older mice and that activated C3 accumulated in the hippocampus.
Improvement seen only in older mice treated with C3-blocking therapy
The complement system is part of the immune system that helps coordinate attacks against invaders like bacteria and viruses. However, complement activation may also play a role in autoimmune diseases. It has been linked to more severe disability in MS.
The system is “tightly controlled, but if it’s not controlled or is overactivated, it can cause damage,” Ramaglia said.
To test whether complement activity was driving the more severe disease features in aged animals, the team used a gene therapy approach to block C3 activation in the brain. They expected that this would help ease symptoms in older animals and “essentially turn an aged mouse into a young [mouse], causing a remission,” Ramaglia said.
The results supported this hypothesis. Only older mice treated with the C3-blocking therapy showed clinical improvement. The treatment had no effect in younger animals, suggesting complement activity is specifically linked to age-related disease worsening.
Taken together, our data identifies complement as a driver of age-dependent progression in [a mouse model] that is relevant to [progressive MS].
Finally, the researchers examined postmortem brain tissue from people with progressive MS to assess whether similar complement activity was present. The team found that patients with greater hippocampal damage showed a greater accumulation of immune cells in the leptomenines and also significantly higher levels of C3.
The findings point to a connection between leptomeningeal inflammation, complement activation, and hippocampal damage in progressive MS. Further studies are underway to determine whether targeting C3 could serve as a therapeutic strategy.
“Taken together, our data identifies complement as a driver of age-dependent progression in [a mouse model] that is relevant to [progressive MS],” the researchers wrote.
The Multiple Sclerosis News Today team is providing virtual coverage of the ACTRIMS Forum 2026 from Feb. 5-7. Go here to see the latest stories from the conference.
