Clinicians and researchers have suspected for years that an aggressive, less-common form of multiple sclerosis (MS) is likely a distinct form of the disease. Now, new research conducted using a more accurate mouse model confirms it.
In a study published Feb. 3 in Brain, scientists from Tisch MS Research Center of New York reported that they had developed the first-ever mouse model for primary progressive MS, or PPMS, which revealed that the disease has a unique pathology distinct from other subtypes. The model and the researchers’ findings clarify that PPMS should be studied separately from other MS subtypes such as secondary progressive MS and could also identify new strategies to treat the condition.
“In a lot of the studies that have been performed, researchers lump secondary and primary progressive MS into one category,” lead author Jamie Wong, Ph.D., told Fierce Biotech in an interview. “Moving forward, based on these results, I think people should be more aware of these differences between primary progressive MS and secondary progressive MS and really try to focus on treating these as two distinct entities.”
PPMS affects between 10% and 15% of all patients with MS. Unlike relapsing remitting MS, the most common form, there is no relief from symptoms after they begin. And unlike secondary multiple sclerosis, which arises after many years of RRMS, PPMS is an initial diagnosis.
The symptoms and pathophysiology of PPMS differ from other forms, too. For instance, patients with PPMS tend to have more sensory symptoms like weakness compared to those with RRMS. The destruction of the myelin sheath also happens in the spinal cord rather than the brain, so MS’ hallmark sclerotic lesions show up there rather than on an MRI of the brain.
While MS is considered to be an autoimmune disease, it’s not clear what causes someone to develop RRMS, PPMS or another subtype. PPMS had long been challenging to study because, unlike other forms of MS, there was no reliable animal model. Researchers generally use mice with autoimmune encephalomyelitis to study MS. But because PPMS appears to be centered on the spine, the model doesn’t reflect the disease.
Since understanding the etiology of PPMS would require a better way to study it, the Tisch researchers first set out to create a more accurate model. To do that, Wong injected cerebral spinal fluid, or CSF, from human donors with PPMS directly into the spinal cords of mice—a technically challenging feat that built upon her experience studying spinal cord injury as a graduate student. The researchers then performed same intrathecal injections on other models using cerebral spinal fluid from patients with other types of MS to compare how the disease progressed.
The researchers were surprised to see that mice injected with the CSF from PPMS patients developed the same weakness and other disabilities seen in the condition. In contrast, the mice who received the CSF from patients with other CSF subtypes didn’t develop symptoms at all. With a clear indication that the CSF from PPMS patients was driving disease in the mice, the researchers had more questions. What was causing the pathology, and how did it differ from other forms of MS?
Filtering out components of the CSF from PPMS patients provided some answers. Size filtration studies, where the elements that make up a substance are separated according to size, showed that the compound causing the disease in the mice was larger than 100 kilodaltons. At around 150 kilodaltons, antibodies seemed like the most likely culprit, Wong explained. And indeed, when the antibodies were removed from the PPMS CSF before it was injected into mice, “that pathogenic capacity of the CSF went away,” she recalled.
“If you remove the antibodies from the PPMS CSF and then inject it into mice, those mice are normal,” Wong said. “There were no pathological effects.”
The scientists reiterated their findings by making PPMS antibodies from the patients’ CSF and injecting those by themselves into the mice. The antibodies alone were able to cause the same disabilities seen in the mice that received the PPMS spinal fluid. “That’s why we came to the conclusion that there are these pathogenic antibodies into the PPMS CSF that are responsible for causing disability and pathology in these mice,” Wong explained.
The mouse model does come with a limitation. It is theoretically possible that it’s not the antibodies themselves causing the disease, but a decrease in factors that help maintain myelin in the central nervous system, the researchers noted. “Although this study supports a role for intrathecal antibodies in PPMS CSF in mediating disease pathophysiology, we cannot exclude the possibility that depleted factors in PPMS CSF could also be contributing to disease pathology in PPMS,” they wrote in the study.
Still, given that the antibodies by themselves could cause symptoms of PPMS and that removing them from the CSF was enough to keep the disease from developing, it appears likely that they’re the source of the problem. Exactly what they’re binding to, though, isn’t yet clear, Wong said.
“The big question everybody wants to know is what these antibodies are binding to, but nobody’s been able to find one single target,” Wong said. In the researchers’ own study, there was no obvious target antigen. Instead, the antibodies seemed to bind robustly across cell types throughout the spinal cord tissue, differing even from one mouse to the next. “It wasn’t all the same, even though the mice all showed disability and hallmark pathology,” Wong said.
What was clear, though, was that the antibodies from the PPMS CSF were highly specific to the spinal cord. The researchers were able to detect every PPMS antibody that they injected on the mouse spinal cords, and none at all in the spinal cords of mice that received antibodies from other subtypes.
“It seems like for some reason these antibodies are more likely to bind to the spinal cord and somehow cause this pathology,” Wong explained. While the scientists don’t know what they’re binding to, “they’re definitely sticking to the spinal cord at a higher likelihood than other forms of MS,” she added.
Future work by Wong’s team will delve into that mechanism, perhaps by manipulating different parts of the antibody and then injecting it into the mice, she said, to see what part might be specifically responsible for triggering symptoms. They may use spatial transcriptomics, a method of profiling gene activity in a tissue sample, to see how the antibodies are influencing gene changes in different cell types.