PURPOSE OF REVIEW: To review novel multiple sclerosis (MS) therapies currently in clinical trials. RECENT FINDINGS: Sixty-seven clinical trials were selected and grouped into the following categories: Bruton's tyrosine kinase inhibitors, remyelinating therapies, immunomodulators, B cell therapies, supplements/microbiome influencers, and cell-directed therapies. Important findings include tolebrutinib's successful trial in nonrelapsing secondary progressive MS that slowed CDP compared to placebo and simvastatin's failure to show an effect on disability in its phase 3 trial. SUMMARY: Multiple strategies are being investigated in MS to address progressive disability, myelin repair, neural protection and treatment refractory disease. Some of these strategies have successfully completed clinical trials giving hope that some of the most vexing aspects of MS will soon have new treatment options.

• Keywords
• Bruton's tyrosine kinase, clinical trials, disease modifying therapies, multiple sclerosis, remyelination,
• MeSH
• Immunologic Factors * therapeutic use   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Multiple Sclerosis * therapy   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Immunologic Factors * MeSH

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS), characterized by inflammation and neurodegeneration. The pathophysiology of MS, especially its progressive forms, involves various cellular components, including microglia, the primary resident immune cells of the CNS. This review discusses the role of microglia in neuroinflammation, tissue repair, and neural homeostasis, as well as their involvement in MS and explores potential therapeutic strategies targeting microglial function. METHODS: A literature search conducted in August 2023 and updated in March 2025, using the PubMed database, focused on articles relating to microglia and MS published in 2018-2025. Additionally, ongoing clinical trials of Bruton's tyrosine kinase (BTK) inhibitors were identified through the ClinicalTrials.gov website in November 2023 and updated in March 2025. RESULTS: Microglia are highly adaptive and exhibit various functional states throughout different life stages and play critical roles in neuroinflammation, tissue repair, and neural homeostasis. Their altered activity is a prominent feature of MS, contributing to its pathogenesis. Imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) provide insights into microglial activity in MS. BTK inhibitors and other novel treatments for MS, including masitinib and frexalimab, show promise in modulating microglial function and influencing the disease progression rate. CONCLUSIONS: The multifaceted roles of microglia in CNS development, immune surveillance, and particularly in the pathogenesis of MS highlight the potential of targeting microglial functions in MS treatment. Emerging research on the involvement of microglia in MS pathophysiology offers promising avenues for developing novel therapies, especially for progressive MS, potentially improving patient outcomes in this debilitating disease.

• Keywords
• central nervous system, disease management, microglia, multiple sclerosis, neuroinflammation,
• MeSH
• Protein Kinase Inhibitors * therapeutic use   pharmacology   MeSH
• Tyrosine Kinase Inhibitors MeSH
• Humans MeSH
• Microglia * drug effects   immunology   metabolism   MeSH
• Agammaglobulinaemia Tyrosine Kinase * antagonists & inhibitors   metabolism   MeSH
• Multiple Sclerosis * drug therapy   immunology   etiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• BTK protein, human MeSH Browser
• Protein Kinase Inhibitors * MeSH
• Tyrosine Kinase Inhibitors MeSH
• Agammaglobulinaemia Tyrosine Kinase * MeSH