Repair, Remyelination, and Progress: What’s Driving MS Innovation in 2025?

Daniel Ontaneda, MD, PhD

In 2024, the field of multiple sclerosis (MS) witness significant advancements in both diagnostic capabilities and treatment options, signaling a transformative year for patient care. One of the most impactful developments was the refinement of the McDonald diagnostic criteria, which embraced a biomarker-driven, molecular approach to viewing the disease. The use of advanced imaging markers like the central vein sign and paramagnetic rim lesions, along with laboratory measures such as kappa free light chains, may enable earlier and more accurate diagnoses of MS, particularly in cases where clinical manifestations are not yet overt.

Nearly a quarter of the way into 2025, the application of these new criteria remains of upmost importance for those in the field, including Daniel Ontaneda, MD, PhD. Ontaneda, an associate professor of neurology at the Cleveland Clinic Lerner College of Medicine, shared insights on some of the most exciting advancements and challenges in the field of MS in 2025. In the discussion, he also talked areas that could see significant growth, including the therapeutic landscape of repairing and remyelinating strategies as the next frontier of MS treatment. Furthermore, he expressed cautious optimism about the growing interest of CAR-T cellular therapeutics, urging for strategic trial designs to ensure meaningful process.

NeurologyLive: What excites you the most in the neurology/MS space in 2025?

Daniel Ontaneda, MD, PhD: The one thing—or actually, two things—are what probably excite me the most. The first hinges on work we’ve been doing, which relates to updating the diagnostic criteria for multiple sclerosis. The paper for this was just submitted, and these criteria, called the 2024 criteria, will be published in 2025. This is going to expand who we can diagnose with multiple sclerosis, which I think is huge for our field. It’s a significant change.

On one side, it’s very positive because people who we previously couldn’t call MS—but who we biologically thought had MS—now we can diagnose. If needed, we can start them on treatment. This is going to be transformative—changing MS from a diagnosis that requires clinical manifestations to one that can be made using specific biomarkers. That’s a big shift for our field. It shows that we’re thinking about the disease more biologically, which is important.

We’ll need to learn how to apply tools like the central vein sign in clinical practice, use paramagnetic rim lesions, and incorporate kappa free light chains—these very specific biomarkers—into our daily work. It’s exciting because there are opportunities for teaching, research, and new methods. But it’s also a bit more complicated, as we’ll need to know more and adapt our approaches. Essentially, it will make diagnosing MS easier in some ways because we’ll have more tools, but it also adds complexity with the new knowledge we’ll need.

The second thing relates to treatment. I think a lot of people will say this, but we’ve historically lacked good treatments for progressive forms of MS. We’ve never had an approved treatment for true secondary progressive MS without activity—it’s been elusive. We’ve had treatments for primary progressive MS, but those trials often involved patients enriched with inflammation, so there’s always been doubt about what was driving the effect.

The results presented at ECTRIMS are incredibly exciting. These showed that targeting a novel pathway in MS, BTK inhibitors (BTKis), actually reduces disability progression, independent of relapses or enhancing lesions. That’s game-changing. In my clinic, the biggest unmet need is for patients in their 40s, 50s, or 60s—patients who are well-controlled on an S1P modulator but continue to worsen. Right now, I have nothing to offer them. BTK inhibitors could change that.

At the ECTRIMS Forum, we also saw an interesting analysis linking BTKi efficacy to the presence of paramagnetic rim lesions. Patients with the highest number of these lesions saw the greatest benefit from BTKis. That’s huge because it connects diagnostic biomarkers like the central vein sign or paramagnetic rim lesions not just to diagnosis and prognosis but also to treatment selection. It reinforces that progressive MS is likely driven by multiple mechanisms, and chronic active lesions are one of them. This progress—having biomarkers that predict treatment response—marks a big step forward for our field.

What is one concept that’s going to explode or take off in 2025?

I think it’s what we hope will explode: repair therapies—repair and remyelination. This is the next frontier, not just for MS but for neuroscience as a whole. How do we repair a damaged central nervous system? That’s the big question.

Several companies are starting trials in remyelination and repair. At ECTRIMS, there was a great Brain Exchange session hosted by Shiv Saidha, MD, MBBCH, and Jiwon Oh, MD, PhD, which made it clear this is where the field is heading. There are already compounds in phase 2 trials targeting specific remyelination pathways. By the end of 2025, I hope we’ll have robust data to show where to take these trials next and how to prove that remyelination and repair are possible in MS.

Are there any concepts we need to pump our excitement on just a bit?

I don’t think there’s anything we need to pump the brakes on entirely, but I’d say we need to be cautious with cellular therapeutics, particularly CAR T-cell therapies. CAR T is a brilliant concept—using engineered T cells to modulate the immune system. It’s a scientifically amazing therapy that could potentially offer long-lasting immunomodulation.

That said, the field has exploded. If you speak to my colleagues, they’ll tell you they’ve been approached by five, six, or even eight companies, all wanting to run CAR T trials. While this reflects how promising the therapy is, it’s also a sign that we might be overextending ourselves.

Most CAR T therapies are anti-inflammatory, and we don’t yet know if they’ll be effective for progressive MS. It’s possible, but we need more clarity before we move forward with so many trials. It would make more sense to test one autologous and one allogeneic CAR T product in large, well-designed trials to see if the mechanism is valid and the treatment works. Right now, there’s a risk of diluting resources and effort across too many small studies.

Cellular therapeutics are exciting, but we need to be strategic. We should focus on understanding the mechanisms and proving the concept before investing too heavily in multiple trials.

Transcript edited for clarity.