Pharmacogenomics of Interferon-ß Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients

Department of Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands.
PLoS ONE (Impact Factor: 3.53). 02/2008; 3(4):e1927. DOI: 10.1371/journal.pone.0001927
Source: PubMed

ABSTRACT Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy.
Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.
Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline.
These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbeta.

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Available from: Tineke C T M van der Pouw Kraan, Aug 06, 2015
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    • "Interferon beta (IFNb) is one of the most frequently used USA Federal Drug Administration approved drugs for the treatment of MS and is the most commonly utilized therapy to prevent exacerbations in relapsing-remitting multiple sclerosis (RRMS) [4]. IFNb has been shown to decrease the rate of relapse by approximately 30% [5] [6], delay progression of disability and lower the number of active lesions on MRI [7]. It is current practice that MS patients start an effective therapy as early as possible in order to prevent neurological disability. "
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    ABSTRACT: Multiple sclerosis (MS) is a demyelinative neuropathy predominantly affecting young people. Currently, interferon beta (IFNβ) is the mainstay treatment for MS. Despite a large effort in recent years, valid biomarkers with predictive value for clinical outcome and response to therapy are lacking. In order to identify predictive biomarkers of response to IFNβ therapy in relapsing-remitting MS patients, we analyzed expression of 526 immune-related genes with the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) on total RNA extracted from peripheral blood mononuclear cells of 30 relapsing-remitting MS patients. We used a Wilcoxon signed-rank test to find an association between certain gene expression profiles and clinical responses to IFNβ. We compared the expression profile of patients who responded to IFNβ treatment (n = 16) and non-responsive IFNβ patients (n = 14). The analysis revealed that the expression of eight genes could differentiate between responsive and non-responsive men (p < 0.005). This differentiation was not evident in women. We analyzed results from an additional cohort of 47 treated and untreated patients to validate the results and explore whether this eight gene cluster could also predict treatment response. Analysis of the validation cohort demonstrated that three out of the eight genes remained significant in only the treated men (p < 0.05). Our findings could be used as a basis for establishing a routine test for objective prediction of IFNβ treatment response in male MS patients.
    Journal of Clinical Neuroscience 01/2015; DOI:10.1016/j.jocn.2014.11.027 · 1.32 Impact Factor
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    • "Similarly, external validity of the study is supported by the presence of genes previously described as biomarkers for IFNB activity. With the exception of the transcript 238704_at, the biomarkers that passed the selection criteria consistently at all three time points, were known as differentially expressed either in the context of therapy with IFNB1a such as IFI44L and ISG15 [8] [9] [11], or in the context of therapy with IFNB1b such as IFIT3 and SN [7] [10], or both IFNB1a and IFNB1b such as EIF2AK2, IFI6, IFI44, IFIH1, IFIT1, IFIT2, MX1, OASL, RSAD2 and XAF1 [6 – 12,14]. There were other frequently cited IFNB biomarkers like Interleukin-8 [17], which Figure 3. Differential expression of 15 transcripts reaching the highest consensus among IFNB treated patients at all three time points (t 1 , t 2 and t 3 ) when compared to the reference (t 0 ). "
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    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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