ACTRIMS 2026: Mouse model mimics form of disability progression
Mice designed to show features of PIRA to aid understanding of condition
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A new mouse model mimics PIRA in multiple sclerosis.
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It shows immune cell clusters, nerve cell damage, and motor deficits.
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The model is a tool to develop new treatments for progressive MS.
Researchers have developed a mouse model designed to reflect the disability worsening that occurs in the absence of relapses for many people with multiple sclerosis (MS).
The model shows key features of this form of disease worsening, known as progression independent of relapse activity (PIRA), including immune cell clusters in specific brain regions, nerve cell damage, and motor problems.
Its developers believe the mouse model will provide scientists with a tool to better understand PIRA and develop treatments to stop it.
Antonella Mini, a PhD student at the University of Miami, discussed the findings in an oral presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2026, being held Feb. 5-7 in San Diego and virtually. Mini’s talk was titled, “Modeling Progression Independent of Relapse Activity (PIRA) with a Transgenic Model of Demyelination Induced by Oligodendrocyte-specific Mitochondrial DNA Damage.”
Disability progresses gradually, even without relapses
Most people with MS are diagnosed with a relapsing form of the disease, marked by periods of MS symptom worsening (relapses) interspersed with periods of remission when symptoms ease.
The traditional view was that for these people, disability worsening was a consequence of symptoms that didn’t completely resolve after relapses. It’s now understood, however, that for many people, disability progression happens gradually over time, even when relapses don’t occur.
Researchers think this progression, known as PIRA, begins at disease onset and continues even when patients are on MS treatments that keep relapses suppressed.
PIRA, thought to be a “major contributor to disability progression,” is driven by chronic, low-grade inflammation inside the brain and spinal cord that contributes to nerve cell damage, Mini said.
New therapies that target these processes are needed to slow or stop MS progression. However, therapeutic development has been hampered by a lack of animal models that capture the key features of PIRA. The most commonly used MS models each have limitations in understanding this form of disease progression.
“There’s no single model that fully recapitulates both neurodegeneration and progressive disease mechanisms,” Mini said. “This creates a major barrier to developing therapies to treat progressive MS.”
The new mouse model was designed to address this limitation.
In MS, the immune system mistakenly attacks and damages myelin, the protective coating surrounding nerve cells. In the brain and spinal cord, myelin is made by cells called oligodendrocytes.
To recreate this myelin loss, or demyelination, in mice, scientists used a genetic tool to gradually damage the mitochondria — the cell’s energy-producing powerhouses — within oligodendrocytes. When mitochondria fail, the oligodendrocytes die and stop producing myelin, ultimately leading to demyelination and neurodegeneration.
The researchers observed that immune cells in the model infiltrated the brain and formed clusters resembling those associated with PIRA. Additional analyses showed that B-cells were the first immune cells to infiltrate the brain and spinal cord.
Mini noted the finding as significant because, despite “B-cells [being] increasingly recognized as key drivers of MS progression,” other MS mouse models are mainly driven by immune T-cells. These mice “may represent a good model to study [B-cell] contribution to disease,” she said.
Blood biomarkers of neurodegeneration were also elevated.
In parallel with these cellular changes, the mice developed motor deficits, which were more pronounced in male animals. Body weight was also reduced in both sexes.
Overall, the findings suggest that the mouse model “recapitulates key features of PIRA-associated disease progression, providing a powerful tool to interrogate related mechanisms,” Mini said.
The researchers are using the model in ongoing experiments to learn more about how some preliminary changes they saw in oligodendrocytes might contribute to disease.
“There’s still much to do in order to understand the function and [disease-driving] role of these oligodendrocyte populations,” Mini said.
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.
