Remyelination therapies are achievable in clinical practice—No

Over the past three decades, drug development and approval for patients with multiple sclerosis (MS) have been very dynamic. However, there are currently no therapies that restore neurological function in individuals with MS who have already accumulated substantial disability. Remyelination therapies may have the potential to address this unmet need, but they face major challenges, some of which are discussed below.

Complex biology of MS

The pathogenesis of MS remains incompletely understood. It is established that inflammation, demyelination, and axonal loss throughout the central nervous system (CNS) are features of all disease stages, ¹ but the sequence and interrelationship of these pathological events are unclear. It is also unknown whether these processes are causally related. Perhaps most pertinent to the question of the feasibility of remyelination therapies is the fact that the critical biological events triggering demyelination and remyelination failure are still being investigated. ² Failure to fully comprehend why oligodendrocyte precursor cells (OPCs) do not differentiate and completely myelinate axons, as well as to identify all inhibitory signals within the CNS, constitutes major obstacles for remyelination therapy.

Additional hurdles to introduce remyelination therapies in MS may arise from unknown disease stage-specific biological events, which will likely complicate clinical trial designs. Most approved disease-modifying therapies (DMTs) either sequester bone marrow-derived leukocytes outside the CNS or reduce their abundance. These therapies are no longer effective in secondary progressive MS (SPMS), indicating that the biology that drives CNS disease towards compartmentalized inflammation has fundamentally changed. ³ However, even in the early relapsing-remitting stage of MS (RRMS), targeting activated leukocytes may reduce disease relapse frequency, but may not significantly benefit the progressive demyelination. For instance, leukocytes subsets secrete trophic factors, including insulin-like growth factor 1 (IGF-1) that promote the formation of OPC. ⁴ Consequently, combining anti-inflammatory therapy with re-myelinating agents could offer both opportunities and challenges.

A comprehensive understanding of these biological mechanisms-and their interplay across disease stages-will be essential for the successful development of remyelination therapies in MS.

Preclinical-to-clinic translation gaps

Numerous remyelination therapies have shown limited effectiveness in clinical trials. One approach targeted LINGO-1 (leucine-rich repeat and immunoglobulin domain-containing Nogo receptor–interacting protein-1), a key inhibitor of oligodendrocyte differentiation and myelination. Opicinumab, a monoclonal antibody against LINGO-1, demonstrated early promise in preclinical and phase 1 studies; however, it failed to show significant clinical benefit in larger phase 2 trials.^5,6 Clemastine (a muscarinic receptor antagonist) modestly improved electrophysiological measures in patients with MS but had limited impact on neurological function. ⁷

Importantly, negative trial outcomes should not be equated with a complete failure to re-myelinate CNS axons. Advanced magnetic resonance imaging (MRI) modalities and visual evoked potentials may suggest evidence of partial myelin repair even when no clinical improvement is observed. However, meaningful therapeutic success must translate into functional improvement. This disconnect suggests remyelination alone may be insufficient, especially in the presence of irreversible axonal damage or complex neural network disruptions. Future therapies must pair myelin repair with neuroprotection and strategies to restore function.

Pharmacological challenges and potential side effects of re-myelinating therapies

Delivering pharmacological agents effectively to the CNS remains a substantial obstacle for remyelination therapies. Both small molecules and monoclonal antibodies face limited CNS penetration due to the restrictive nature of the blood–brain barrier (BBB). Achieving therapeutic concentration often requires high systemic doses, which can increase the risk of off-target effects and systemic toxicity. An example of failed drug delivery is opicinumab, which showed no significant improvement in a placebo-controlled phase 2 clinical trial.^5,6 Presently, strategies such as the genetic re-engineering of therapeutic antibodies, including the addition of transferrin receptors or insulin receptors, ⁸ or the targeted disruption of the BBB using focused ultrasound ⁹ may mitigate the issue of limited CNS penetration.

Finally, some remyelination therapies may have broader pharmacological effects on the nervous system, rather than being specifically targeted at remyelination. For example, clemastine showed some modest improvements in electrophysiological measures but also affected other biological pathways, leading to side effects such as fatigue.

Lack of validated biomarkers for remyelination

A major barrier to advancing remyelination therapies in MS is the lack of validated, reliable biomarkers that can accurately detect and quantify remyelination in vivo. Conventional imaging modalities, like standard MRI, are sensitive to gross changes in lesion volume and inflammation but not specific for myelin content or repair. Advanced MRI methods (e.g. magnetization transfer ratio, myelin water imaging, and diffusion tensor imaging) offer improved sensitivity to myelin changes, but lack standardized criteria and widespread validation for use as surrogate endpoints. ¹⁰ Electrophysiological measures such as visual evoked potentials can provide indirect evidence of improved conduction along demyelinated pathways, but they do not directly measure remyelination and may be influenced by other factors such as axonal integrity. The absence of robust, validated biomarkers complicates trial design, and may contribute to the disconnect between biological repair and clinically meaningful outcomes.

Patient population heterogeneity

Another significant challenge in developing remyelination therapies is the heterogeneity of the MS patient population. MS varies widely in age at onset, disease duration, lesion burden, and extend of irreversible axonal loss. Some individuals may have a disease course dominated by active inflammation and demyelination, while others may have entered a chronic, neurodegenerative phase with limited repair capacity. This variability affects both response to therapies and the ability to detect treatment effects. Patients with advanced disease may lack viable axons or OPCs to support remyelination, while those with early-stage disease or active lesions are more likely to benefit but are often underrepresented in clinical studies. Careful patient selection, stratification by biomarkers of disease activity and repair capacity, and individualized therapeutic approaches will be crucial for optimizing the effectiveness of remyelination therapies and for accurately interpreting trial outcomes.

Conclusion

While remyelination therapies hold promise for MS, significant challenges remain, including gaps in our understanding of MS biology, difficulties with drug delivery into the CNS, lack of validated biomarkers, and complexities in patient selection. Future research will require combination treatments, improved CNS targeting, robust biomarkers, and careful patient stratification to translate biological repair into meaningful clinical improvement in MS.