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: 3.23). 02/2008; 3(4):e1927. DOI: 10.1371/journal.pone.0001927
Source: PubMed


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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    • "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 · 1.38 Impact Factor
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    • "14 significantly upregulated genes were identified at all three time points. These had also previously been shown to be differentially expressed upon treatment with IFN-β-1a (IFI44L, ISG15) [46], [47], IFN-β-1b (IFIT3, SN/SIGLEC1) [48] or both (EI2AK2, IFI6, IFI44, IFIH1, IFIT1, IFIT2, MX1, OASL, RSAD2 and XAF1) [46]–[50]. Further IFN-β treatment-related biomarkers like IL-8 were identified only directly after onset of therapy. "
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    ABSTRACT: The drug edelfosine is a synthetic analog of 2-lysophosphatidylcholine. Edelfosine is incorporated by highly proliferating cells, e.g. activated immune cells. It acts on cellular membranes by selectively aggregating the cell death receptor Fas in membrane rafts and interference with phosphatidylcholine (PC) synthesis with subsequent induction of apoptosis. Edelfosine has been proposed for the treatment of autoimmune diseases like multiple sclerosis (MS). Earlier studies on the animal model of MS, experimental autoimmune encephalomyelitis (EAE), have generated first evidence for the efficacy of edelfosine treatment. However, it is unknown if the previously described mechanisms for edelfosine action, which are derived from in vitro studies, are solely responsible for the amelioration of EAE or if edelfosine may exert additional effects, which may be beneficial in the context of autoimmunity. Since it was the purpose of our studies to assess the potential usefulness of edelfosine for the treatment of MS, we examined its mechanism/s of action on immune functions in human T cells. Low doses of edelfosine led to a decrease in homeostatic proliferation, and further studies of the mechanism/s of action by genome-wide transcriptional profiling showed that edelfosine reduces the expression of MHC class II molecules, of molecules involved in MHC class II-associated processing and presentation, and finally upregulated a series of type I interferon-associated genes. The inhibition of homeostatic proliferation, as well as the effects on MHC class II expression and -presentation, and the induction of type I interferon-associated genes are novel and interesting in the context of developing edelfosine for clinical use in MS and possibly also other T cell-mediated autoimmune diseases.
    PLoS ONE 03/2014; 9(3):e91970. DOI:10.1371/journal.pone.0091970 · 3.23 Impact Factor
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    • "Interferons (IFNs) were the first agents to show clinical efficacy in relapsing-remitting multiple sclerosis (RRMS). Interferon beta (IFN-β) decreases clinical relapses, reduces brain disease activity, and possibly slows down progression of disability (1). "
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    ABSTRACT: Treatment with interferon beta (IFN-β) induces the production of binding antibodies (BAbs) and neutralizing antibodies (NAbs) in patients with multiple sclerosis (MS). NAbs against IFN-β are associated with a loss of IFN-β bioactivity and decreased clinical efficacy of the drug. The objective of this study was to evaluate the incidence and the prevalence of binding antibodies (BAbs) and neutralizing antibodies (NAbs) to IFN-β in MS patients receiving CinnoVex, Rebif, or Betaferon. The presence of BAbs was studied in serum samples from 124 MS patients using one of these IFN-β medications by ELISA. The NAbs against IFN-β were measured in BAb-positive MS patients receiving IFN-β using an MxA gene expression assay (real-time RT-PCR). Of the 124 patients, 36 (29.03%) had BAbs after at least 12 months of IFN-β treatment. The proportion of BAb+ was 38.1% for Betaferon, 21.9% for Rebif, and 26.8% for CinnoVex. Five BAb-positive MS patients were lost to follow-up; thus 31 BAb-positive MS patients were studied for NAbs. NAbs were present in 25 (80.6%) of BAb-positive MS patients receiving IFN-β. In conclusion, the three IFN-β preparations have different degrees of immunogenicity.
    Journal of Korean medical science 12/2013; 28(12):1801-6. DOI:10.3346/jkms.2013.28.12.1801 · 1.27 Impact Factor
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