RNA expression signatures in peripheral blood cells of interferon-beta 1a (IM) treated MS patients disclose differentially expressed genes of therapy predicting value
Objective: This longitudinal systematic gene expression study focused on the disease multiple sclerosis (MS) and the effects of medication by interferon-beta-1a (IFNß1a). It was the aim to detect surrogate markers for therapeutic intervention (discern RNA-profiles derived from (non-)responders to treatment) in human PBMCs and to infer accessory regulatory pathways of applied MS drug.
Background: interferon-beta (IFNbeta) therapy in patients with MS has proven efficacious, but appears suboptimal in terms of therapy responder rate and adverse events. Large scale analysis of peripheral blood messenger RNA transcripts over time provide an unprecedented view of the complexity of studied disease and generates a huge data set that shall serve molecular group classifications.
Method: Employing the Affymetrix HGU133AB set (45.000 transcripts), we performed a full genome study monitoring 21 patients receiving IFNbeta1a (i.m., once weekly) over a period of 24 months. Samples were collected and directly processed before first treatment (t0), after 1 week, 4 weeks, 1 and 2 years. Systematic time-dependent transcriptome analyses were realized (supervised learning, interaction exploring and literature-mining tools). Permutation analyses (R software) provide degrees of genuinely differently expressed genes derived from pair-wise comparisons with t0. Therapy prognosis analyses (decision trees) of responder status and paraclinical parameters have been started. Absolute expression values and ratios were used as discriminating variables.
Results: IFNbeta1a pathway related accessory molecules like decreased Dual Phosphatase6 (DUSP6; MAPK1-inhibitory) and increased Prokinecitin2 (PROK2; MAPK1-inducing) expression in the majority of analyzed individuals are promising candidates to be actively involved in IFN regulated effects. First results of the prognostic models disclose a set of interferon responsive and apoptosis related genes that perform reasonably well with a good outcome at 1 month into therapy.
Relevance: The dynamic expression changes of individual RNA profiles reflect the interweaving of disease and therapy course complexities. Adjacent to established IFNbeta-related markers such as e.g. MX1, OAS, STAT1, accessory molecules of compensatory pathways could be an important ancillary therapeutic prognostic tool, which needs to be validated in additional MS cohorts.