Pathobiology-guided diagnostic advances, biomarker discovery, and emerging therapeutic strategies in progressive multiple sclerosis.

Abstract

Progressive multiple sclerosis (PMS) represents a severe and disabling form of MS characterized by a gradual accumulation of neurological impairment and limited responsiveness to conventional disease-modifying therapies. Unlike the relapsing forms of the disease, progressive MS is driven not only by peripheral immune dysregulation but also by persistent neuroinflammation, microglial activation, mitochondrial dysfunction, and progressive neurodegeneration within the central nervous system. These complex and overlapping pathogenic mechanisms contribute to irreversible axonal loss and pose significant challenges for therapeutic intervention. Although recent advances in immunomodulatory treatments have improved outcomes for some patients, currently available therapies provide only limited benefits in slowing disease progression. Consequently, the identification of novel molecular pathways and therapeutic targets has become a major focus in the development of more effective strategies for progressive MS. Rapid progress in understanding the cellular and molecular basis of disease progression has facilitated the exploration of innovative therapeutic approaches, including targeted immunotherapies, neuroprotective agents, remyelination-promoting strategies, and emerging cell-based interventions. Here, in this review, we summarize current advances in the therapeutic landscape of progressive MS, highlighting recently approved treatments as well as promising agents under clinical investigation. Particular emphasis is placed on the underlying mechanisms of action of these therapies and their potential to modify disease progression, restore neural function, and support the development of personalized treatment strategies for patients with PMS.