Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis

Interferon beta (IFN beta) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFN beta-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFN beta's pleiotropic mechanisms of action. Genes involved in immune regulation, mitochondrial fatty acid metabolism and antioxidant activity were discovered. Plausible mediators of neuronal preservation included NRF2, downregulation of OLA1, an antioxidant suppressor, and the antioxidant gene ND6, implicated in optic neuropathy and MS-like lesions. Network analysis highlighted IKBKE, which likely has a role in both viral response and energy metabolism. A comparative analysis of therapy-naive MS-and IFN beta-associated gene expression suggests an IFN beta insufficiency in MS. We observed more gene expression changes in longterm treatment than during acute dosing. These distinct short-and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFN beta treatment effects were developed and subsequently confirmed in independent IFN beta-1b-treated MS studies, but not in glatiramer acetate-treated patients.