Investigational approaches to multiple sclerosis therapy.

PURPOSE OF REVIEW: Multiple sclerosis (MS) research is entering a new therapeutic era. Beyond relapse rate reduction, the prevention of disability progression and, ideally, even the avoidance of disease development are now being formulated as new therapeutic goals. This review summarizes emerging treatment strategies spanning next-generation immunomodulation, Epstein-Barr virus (EBV) targeted interventions, remyelination agents, and cell-based therapies. RECENT FINDINGS: Central nervous system (CNS) penetrant Bruton's tyrosine kinase (BTK) inhibitors show early indications of slowing progression by targeting compartmentalized inflammation. Fc-silent CD40L blockade offers a non-depleting alternative and suppresses magnetic resonance imaging (MRI) activity in a phase 2 trial. EBV-directed strategies, including adoptive T-cell therapy and prophylactic or therapeutic vaccines, represent initial attempts to modify a likely causal driver of MS. Remyelination candidates including clemastine, selective M1 muscarinic receptor antagonists and other emerging agents, demonstrate biological activity but limited clinical benefit. Cell-based approaches, such as mesenchymal stem cell derived neural progenitors (MSC-NPs) and CD19 or B-cell maturation antigen (BCMA) targeted chimeric antigen receptor T-cell (CAR-T) constructs, remain early phase but show initial biological signals. SUMMARY: These advances mark a shift toward precision immunomodulation, causal targeting, and CNS repair, with BTK inhibitors and CD40L blockade advancing as promising candidates to address progression in MS.