Myelin repair in progressive MS is finally moving from theory to realistic clinical paths—thanks in part to neural stem cell research led by Dr. Luca Peruzzotti Jametti (University of Cambridge / Imperial College London). In this conversation, he explains why remyelination matters, how stem cells help (beyond cell replacement), and what timelines are realistic for trials that could change daily life for people with progressive MS.
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Introduction & Personal Motivation
Could you introduce yourself and share what inspired you to work on neural stem cell therapies for MS?
Dr. Luca Peruzzotti Jametti – Neurologist & Group Leader: I’m a neurologist trained in Italy and the UK. My lab focuses on MS, neuroinflammation, and new treatments. Early collaborations with Prof. Stefano Pluchino drew me into neural stem cell work—first in stroke and then MS—because we saw overlapping biology, like “virtual hypoxia,” between stroke lesions and progressive MS.
What drew your attention specifically to progressive MS and its challenges?
Dr. Luca Peruzzotti Jametti: Beyond relapses, patients develop progression independent of relapse activity (PIRA); inflammation becomes compartmentalized inside the CNS. Resident immune cells—microglia—drive this chronic state. We need therapies that act within the brain, not only treatments that block peripheral immune cells.
Your current team & collaborations (e.g., RESTORE)?
Dr. Luca Peruzzotti Jametti: From early animal work to non-human primates and now a phase-1 trial (2023, Cell Stem Cell) in progressive MS, we’re building toward phase-2 with support from the Progressive MS Alliance and a new consortium.
Understanding the Damage in MS
What happens during a relapse vs. PIRA?
Dr. Luca Peruzzotti Jametti: Relapses come from peripheral immune cells entering the brain; many DMTs reduce this traffic. PIRA occurs when inflammation becomes trapped inside the CNS—microglia stay activated and slowly drive disability, even without relapses.
The role of myelin—and what happens when it’s damaged?
Dr. Luca Peruzzotti Jametti: Myelin insulates axons like the plastic around a wire, enabling fast, efficient signaling. In MS, immune attacks strip this coating, causing conduction block and, over time, axonal loss. Steroids can hasten recovery in acute inflammation, but repeated damage accumulates disability.
Why is myelin repair so limited in progressive MS?
Dr. Luca Peruzzotti Jametti: Two big reasons: (1) Age—most progressive MS patients are older, and regenerative capacity declines. (2) Human-specific constraints—our brains don’t recruit precursors as readily as rodents; repair steps are blocked at multiple stages.
Which cells remyelinate—and what goes wrong?
Dr. Luca Peruzzotti Jametti: OPCs (oligodendrocyte precursor cells) should migrate, proliferate, and differentiate into oligodendrocytes. In MS, blocks can occur at migration, proliferation, differentiation, or axon-wrapping; lesion stiffness, axonal signals, and ongoing inflammation further hinder success.
Can restoring myelin prevent—or even reverse—neurodegeneration?
Dr. Luca Peruzzotti Jametti: Preventing degeneration by restoring myelin early looks feasible; several trials aim to enhance remyelination. Reversal is still uncertain, but earlier intervention could preserve resilience and delay progression.
Stem Cell–Based Repair Strategies
What are NSCs and how do induced NSCs (iNSCs) differ?
Dr. Luca Peruzzotti Jametti: Neural stem cells (NSCs) are brain-specific and can become neurons, oligodendrocytes, or astrocytes. Our phase-1 used allogeneic fetal/embryonic-derived NSCs, requiring immunosuppression. Induced NSCs (iNSCs) are made from a patient’s own cells (e.g., skin fibroblasts reprogrammed using Yamanaka-style factors), reducing rejection risk and enabling personalized products.
How do these cells help repair damage?
Dr. Luca Peruzzotti Jametti: Not only by potential cell replacement but through paracrine effects—they sense inflammation, home to lesions, and secrete molecules that dampen immune activity, promote regeneration, and detoxify pro-inflammatory metabolites to make the lesion micro-environment more repair-friendly.
“Paracrine effect” in simple words?
Dr. Luca Peruzzotti Jametti: It’s the healing signals cells release to help nearby cells—reducing inflammation and nudging the tissue toward repair even if the transplanted cells don’t fully replace lost ones.
New myelin vs. immune modulation—what looks most promising?
Dr. Luca Peruzzotti Jametti: Both matter. Our strongest, most consistent evidence is the immune-modulating effect. For new myelin, controlling inflammation is key; in low-inflammation models, NSCs can generate myelin, but heavy inflammation blocks differentiation.
For true remyelination, we still face the hurdles I mentioned earlier – aging, the lesion environment, inflammation itself. So stem cells may first calm the environment, and then indirectly promote repair. In the future, combining stem cells with other approaches, such as metabolism-targeted therapies, might maximize both effects.
Safety of human NSC transplantation so far?
Dr. Luca Peruzzotti Jametti: In two independent progressive-MS phase-1 studies—one using intraventricular neurosurgical delivery and one via therapeutic lumbar puncture—no major adverse effects were observed, even in participants with higher disability (EDSS). This safety profile supports moving to phase-2.
Realistic Perspectives & Clinical Outlook
When might we see the first larger clinical trials?
Dr. Luca Peruzzotti Jametti: Rough estimate: 5–10 years (could be sooner or later). We must progress methodically through safety, dosing, and then efficacy—rushing risks harming patients and the field.
Biggest hurdles—scientific, regulatory, practical?
Dr. Luca Peruzzotti Jametti: All of the above: complex regulation, manufacturing logistics for advanced therapy medicinal products, standardized thawing/processing across centers, and consistent injection protocols. Historical timelines for biologics (e.g., alemtuzumab) show how long translation can take—cells are even more complex.
For whom would therapy be used? After aHSCT?
Dr. Luca Peruzzotti Jametti: Likely most valuable in progressive MS or when PIRA emerges; early relapsing disease already has effective options. Sequential use after aHSCT is plausible (not simultaneously): aHSCT first; if progression occurs later, consider NSC therapy.
Relation to other strategies (e.g., targeting mitochondrial metabolism)?
Dr. Luca Peruzzotti Jametti: My lab focuses heavily on bioenergetics in lesions—aiming to make the brain “fitter” metabolically. Think stacked approaches: stem cells + metabolic targets + other innovations coming through the pipeline.
How realistic is reversing disability in 10–15 years?
Dr. Luca Peruzzotti Jametti: Optimistic—yes. Multiple lines of research are advancing in parallel; important breakthroughs don’t arrive linearly but in waves.
Quickfire Q&A Session
Complete the sentence: "For me, multiple sclerosis is...."
“For me, MS is fascinating.”
What development would you like to see in the field of MS in the next 5 years?
“Slowing down progression efficiently.”
Farewell
What message would you like to share with people living with progressive MS, who may feel left behind by current therapies?
“We’re here for you, always.”
How and where can interested people follow your research activities?
Follow the team via the Progressive MS (Cambridge) Facebook page, BlueSky, and Cambridge lab pages. You can also follow our work through the Progressive MS Alliance and the RESTORE consortium.
References & Related Episodes/Topics
See you soon and try to make the best out of your life,
Nele
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