Genomic effects of once-weekly, intramuscular interferon-beta 1a treatment after the first dose and on chronic dosing: Relationships to 5-year clinical outcomes in multiple sclerosis patients
ABSTRACT 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.
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.
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.
Gene expression is a valuable tool for understanding the molecular mechanisms of IFN-beta action in MS patients.
- SourceAvailable from: Hans-Jürgen Thiesen
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- "In return, the exploration of potential targets and PBMC biomarkers arising from one year therapy monitoring is absolutely unbiased, in contrast to knowledge-based models. An ambitious highthroughput gene expression profiling project for long-term IFNB therapy has been recently performed by Weinstock-Guttman et al.  comprising 11 timecourse checkpoints and extending to 12 months of therapy with IFNB1a. Our study tries to partially reproduce this kind of exploratory analysis in a sample of the German population for IFNB1b. "
ABSTRACT: Despite its generalized use as drug therapy for multiple sclerosis (MS), the molecular mechanisms of action of interferon beta (IFNB) are still poorly understood. IFNB therapy is long-termed and clinical effects are not immediate, therefore reliable early biomarkers for IFNB activity should maintain a differential expression over time, but longitudinal studies at a transcriptional level have been rare. Microarrays were used to monitor 18 IFNB1b treated MS patients at four time points spanning a period of 1 year. Genes showing in the majority of patients the greatest and most consistent changes in their expression levels were studied. Interferon regulated genes were significantly overrepresented. Fifteen markers were differentially expressed during all three time points and followed a consistent time course pattern: EIF2AK2, IFI6, IFI44, IFI44L, IFIH1, IFIT1, IFIT2, IFIT3, ISG15, MX1, OASL, RSAD2, SN, XAF1 and the marker 238704_at. Except for the last one, these biomarkers were all formerly identified as being indicative for IFNB activity. Expression changes were both early detectable and long lasting and could thus be optimal biomarkers for IFNB activity in long-term studies. Other known biomarkers of IFNB activity were found to be differentially expressed just for certain periods after therapy onset: Interleukin-8 was a short lasting marker and changes in STAT1 were detected with delay.Autoimmunity 11/2009; 43(2):172-8. DOI:10.3109/08916930903219040 · 2.75 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory, disabling disease of the CNS. A recent study has estimated the annual cost of MS in Europe at euro12.5 billion. There is no definitive cure for the disease. Immunomodulatory therapies, such as IFN-beta and glatiramer acetate, are only partially effective. Various new therapies in the final stages of clinical trials are being developed in the absence of efficacy biomarkers. Hence, there is a pressing need for identification of MS treatment response biomarkers. The focus of the multicenter research initiative United Europeans for the development of pharmacogenomics in MS (UEPHA*MS) is to promote and improve training opportunities in the novel supradisciplinary area of pharmacogenomics, biomarker research and systems biology applied to MS. UEPHA*MS is a Marie Curie Initial Training network funded by the 7th Framework Programme of the European Commission. The main scientific goals of this network are both to enhance our knowledge of the mechanisms determining response outcomes of existing immunomodulatory therapies and to identify novel therapeutic opportunities. UEPHA*MS is composed of 11 internationally recognized research teams from five countries with an assortment of expertise in complementary disciplines. The UEPHA*MS network will provide a coherent and internationally competitive platform for the training of young scientists based on multidisciplinary state-of-the-art laboratory-based and network-wide activities. This network will be instrumental in priming young scientists for Europe's collective effort toward improved provision of healthcare based on personalized medicine.Pharmacogenomics 06/2009; 10(5):885-94. DOI:10.2217/pgs.09.33 · 3.43 Impact Factor
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ABSTRACT: We had reported that immune cells from relapsing remitting multiple sclerosis (RR-MS) patients secrete low levels of BDNF and that there is a defective regulation of its secretion via DC40. We now studied the effect of interferon-beta (IFN-beta1) on the secretion and regulation of BDNF from immune cells in patients with RR-MS. The PBMCs of IFN-beta1a treated RR-MS patients secreted higher BDNF levels vs. untreated patients. Anti CD40 mAb stimulation of PBMCs of IFN-beta1a treated patients upregulated the BDNF levels. There was no significant effect of CD40 stimulation on PBMCs of untreated patients. CD40(+) expression on CD14(+) cells was higher in IFN-beta treated patients vs. untreated patients. In vitro treatment with IFN-beta1a of PBMCs from healthy controls and untreated patients led to a significant increase in CD40 expression on CD14(+) cells in both groups. The addition of IFN-beta1a to CD40 stimulated PBMCs of untreated patients restored the up regulatory effect of CD40 stimulation on BDNF levels. Therefore, reduced BDNF secretion from PBMCs and defective regulation effect of CD40 stimulation on BDNF levels in untreated RR-MS are reversible by therapy with IFN-beta1a.Journal of neuroimmunology 06/2009; 211(1-2):114-9. DOI:10.1016/j.jneuroim.2009.04.004 · 2.79 Impact Factor