The next big breakthrough in multiple sclerosis (MS) will be preventing neuroaxonal damage and loss and promoting repair of the process that causes disability [1.]
While current disease modifying therapies (DMTs) are very effective at controlling focal inflammation, they have only modest efficacy against the neurodegenerative component of the disease [1.] “Progression independent of disease activity is the most important problem that we need to solve,” said Professor Ludwig Kappos during his Charcot Lecture at ECTRIMS 2025.
Contrary to what was previously thought, progression is not exclusively a late-stage process but can occur early in the course of the disease, leading to widespread tissue loss [2.] Therefore, novel therapeutic interventions are needed to prevent or reduce neuroaxonal damage and promote myelin repair [2.]
“We are primarily studying regeneration, as it is a major issue not only in MS but across the entire field of neurology,” Dr. Christopher Elnan Kvistad of Haukeland University Hospital in Bergen, in Norway, told us. “In neurology we can prevent diseases, alleviate symptoms, and provide rehabilitation, yet we cannot achieve regeneration following injury to the central nervous system (CNS). This remains a critical challenge in MS.”
The Uphill Race to Reverse Damage
Cell-based therapies represent a promising therapeutic pathway for reversing neurological damage in MS (see also our Spotlight on CAR T cells). One such approach involves the mesenchymal stem cells (MSCs). MSCs are adult stem cells that have the capacity to renew themselves and differentiate into different cell types [3.] They can be isolated from several tissues, such as the bone marrow and umbilical cord [3.] Moreover, MSCs seem to have neuroprotective, immunomodulatory, and anti-inflammatory properties [4.]
In rats with induced stroke, MSCs derived from the human umbilical cord migrate toward the injury site and differentiate into neuronal and glial cells [5.] But can we expect the same in humans?
We asked Dr. Kvistad: “In our study, human bone marrow MSCs were sourced from the SMART-MS biobank. The trial lasted one year and a half and was completed in 2025. We administered the MSCs intrathecally via lumbar puncture in a randomised-control trial, with a cross-over design ensuring that all 18 people with progressive MS received treatment, but at different time points. The primary endpoint of our trial was the measurement of combined evoked potentials – a composite score of visual, somatosensory and motor evoked potentials – at 6 months to assess nerve conduction velocity, serving as a parameter for myelin integrity and axonal regeneration. Although no significant difference was observed between the treatment and placebo groups, the group receiving the stem cells showed a significant reduction in brain atrophy after 6 months and lower levels of glial fibrillary acidic protein (GFAP) – an inflammatory marker – as well as decreased inflammation in cerebrospinal fluid. However, these findings were transient: they were not sustained at 12 months.”
Similar results were reported in an Italian study, conducted at San Raffaele Hospital in Milan, which involved 12 participants with progressive MS and evidence of disease progression [6.] The phase 1 clinical trial showed that patients who received the highest dosage of human foetal neural precursor cells transplanted intrathecally showed a lower rate of brain atrophy [6.]
How did the patients feel? “At the end of our study, after one year and a half, we asked the participants about their experience,” says Dr. Kvistad. “The feedback was varied: seven of the 18 reported less fatigue, more energy, and improved mobility, while four patients felt more stable. However, five patients experienced progression as before, and two experienced increased worsening.”
What adverse events occurred? “After the injection, we observed local inflammatory reactions,” continues Dr. Kvistad. “Ten people had low back pain, nine had fever, and seven showed abnormalities on magnetic resonance imaging (MRI) in the lumbar area. One person developed arachnoiditis – an inflammation of one of the protective membranes surrounding the spinal cord – with a chronic pain. Therefore, these results suggest caution for future studies with intrathecal MSCs involving people with MS.”
Bone Marrow-Derived Cellular Therapy
Parallel research investigates the bone marrow’s capacity for neurological repair. We spoke to Dr. Claire Rice of the University of Bristol and Southmead Hospital, who said, “We’ve been interested in exploring the potential of bone marrow therapies for quite a while. The interest has been compounded by the observation that several disease-modifying therapies for MS work by controlling cell trafficking originating from the bone marrow.”
Previously, Dr Rice and colleagues ran a phase I study that confirmed the safety of autologous bone marrow infusion in people with progressive MS [7.] Participants underwent a bone marrow harvest. The marrow was then filtered and re-infused intravenously. The study measured the global evoked potential of the six patients involved – a composite score assessing how fast electrical signals travel through multiple central nervous system pathways. The global evoked potential, which represents a multimodal functional readout of CNS function, improved in all the patients. These findings show a potential reparative effect of the autologous bone marrow infusion [7.]
Following on from this, the team conducted the randomised, double-blind, placebo-controlled ‘ACTiMuS’ study which included 77 participants with progressive MS. The trial met its primary outcome, as Dr Rice tells us, “We observed that the infusion of autologous bone marrow was associated with reduced rate in change of the global evoked potential at 12-months.”
Identifying the underlying mechanisms of action and the specific cell populations involved will be essential to advancing future research and improving clinical outcomes for people with progressive MS.
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Written by Stefania de Vito
Special thanks to Dr. Christopher Elnan Kvistad (Haukeland University Hospital in Bergen, Norway) and Dr. Claire Rice (Bristol Medical School, University of Bristol and North Bristol NHS Trust) for their insights.
References
[1] Bittner S & Zipp F Current Opinion in Neurology 2022; 35(3): 293-298.
[2] Sabatino JJ et al. Annals of Neurology 2025; 98(2): 317-328.
[3] Ding DC, Shyu WC, and Lin S-Z. Cell transplantation 2011; 20(1): 5-14.
[4] Ytterdal M et al. PloS One 2026; 21(4): e0347119.
[5] Ding, DC et al. Neurobiology of Disease 2007; 27(3): 339-353.
[6] Genchi A et al. Nature Medicine 2023; 29(1): 75-85.
[7] Rice CM et al. Clinical Pharmacologicy & Therapeutics 2010; 87(6): 679–85.