Interferon-beta-1b-induced short- and long-term signatures of treatment activity in multiple sclerosis.
Interferon beta (IFNβ) reduces disease burden in relapsing-remitting multiple sclerosis (MS) patients. In this study, IFNβ-1b-treated MS patient gene expression profiles and biological knowledgebases were integrated to study IFNβ'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 IFNβ-associated gene expression suggests an IFNβ insufficiency in MS. We observed more gene expression changes in long-term treatment than during acute dosing. These distinct short- and long-term effects were driven by different transcription factors. Multi-gene biomarker signatures of IFNβ treatment effects were developed and subsequently confirmed in independent IFNβ-1b-treated MS studies, but not in glatiramer acetate-treated patients.
1] Global Medical Affairs, Bayer HealthCare Pharmaceuticals, San Francisco, CA, USA [2] International Review of Investigational Science, Lafayette, CA, USA.
E
E
Croze
K D
KD
Yamaguchi
V
V
Knappertz
A T
AT
Reder
H
H
Salamon
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D015536:Down-Regulation; D005227:Fatty Acids / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000068576:Interferon beta-1b; D016899:Interferon-beta / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009245:NADH Dehydrogenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome
D000276:Adjuvants, Immunologic; D000975:Antioxidants; D054316:Biomarkers, Pharmacological; D005227:Fatty Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D014157:Transcription Factors; D000068576:Interferon beta-1b; D016899:Interferon-beta; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase; D051550:I-kappa B Kinase; C496565:IKBKE protein, human; D000251:Adenosine Triphosphatases; D019204:GTP-Binding Proteins; C522732:OLA1 protein, human