Genomic Effects of Once-Weekly, Intramuscular interferon-beta1a Treatment After the First Dose and on Chronic Dosing: Relationships to 5-year Clinical Outcomes in Multiple Sclerosis Patients

J Neuroimmunol. 2008 Dec 15;205(1-2):113-25. doi: 10.1016/j.jneuroim.2008.09.004. Epub 2008 Oct 23.

Abstract

Purpose: To characterize gene expression in multiple sclerosis (MS) patients after the first dose and chronic dosing of 30 microg, once weekly, intramuscular interferon-beta1a (IFN-beta) and to delineate the pharmacogenomic differences between Good Responders and Partial Responders to IFN-beta therapy.

Methods: The treatment responses after the first IFN-beta dose and chronic IFN-beta dosing were assessed in 22 relapsing MS patients (17 females, 5 males; average age: 41.5+/-SD 10.4 years). Gene expression profiles in peripheral blood mononuclear cells were obtained prior to treatment and at 1, 2, 4, 8, 24, 48, 120, 168 h after the first IFN-beta dose and at 1, 6 and 12 months after chronic dosing with once-weekly 30 microg IFN-beta-1a intramuscularly. Repeated measures statistics with false discovery rate control were used. The functional characteristics, biological pathways and transcription factor sites were analyzed.

Results: Of the 1000 genes modulated following the first dose and upon chronic dosing of IFN-beta in MS patients, approximately 35% were up-regulated and 65% were down- regulated; the percentage of modulated genes in common was approximately 50%. The expression of the pharmacodynamic mRNA markers of IFN-beta effect showed differences in time profiles for the Good Responder and Partial Responders to IFN-beta therapy and the Jak-STAT, TNFRSF10B, IL6, TGFbeta, retinoic acid and CDC42 pathways were differentially modulated. The patients with side effects to therapy showed differences in the TGFbeta1, IFNG/STAT3 and TNF pathways.

Conclusions: Gene expression is a valuable tool for understanding the molecular mechanisms of IFN-beta action in MS patients.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Chronic Disease
  • Cluster Analysis
  • Drug Administration Schedule
  • Female
  • Gene Expression / drug effects
  • Gene Expression Profiling / methods
  • Genome, Human / drug effects*
  • Humans
  • Immunologic Factors / administration & dosage*
  • Injections, Intramuscular / methods
  • Interferon-beta / administration & dosage*
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / pathology
  • Oligonucleotide Array Sequence Analysis / methods
  • Time Factors
  • Treatment Outcome

Substances

  • Immunologic Factors
  • Interferon-beta