Combination therapy dramatically promotes remyelination.

Multiple sclerosis (MS) is an immune-mediated disease in the central nervous system that is characterized by demyelination, axonal degeneration, and progressive neurological disability and is so far incurable. Current medications are predominantly immune-targeted but fail to prevent disease progression due to their inability to actively promote remyelination. Small molecules have been reported to promote myelin regeneration but their therapeutic efficacy is limited by insufficient immune modulation. Thus, the strategies achieving both immunomodulation and active myelin regeneration are highly desired. Here, we investigated a combination therapy (CT) for MS designed to simultaneously modulate immune responses and promote oligodendrocyte precursor cell differentiation and in situ remyelination in an experimental autoimmune encephalomyelitis mouse model. Remarkably, CT suppressed acute inflammatory activity, activated the signaling pathways for myelin development, induced the expression of myelin-related genes, and significantly promoted remyelination and the recovery of motor performance. Furthermore, a reduced immunomodulator dosage or shorter treatment duration with small-molecule drugs achieved comparable symptom reversal. Our findings demonstrate the potential of CT to address complex pathobiology and lay a foundation for developing novel therapeutic strategies for MS.