small-RNA-Seq in four experimental epilepsy models. Circulating microRNAs and isomiRs as biomarkers for the initial insult and epileptogenesis in four experimental epilepsy models – The EPITARGET study

Background – Structural epilepsies can manifest months or years after the occurrence of an initial epileptogenic insult, making them amenable for secondary prevention. However, development of preventive treatments has been challenged by a lack of biomarkers for identifying the subset of individuals with the highest risk of epilepsy after the epileptogenic insult. Methods – Four different rat models of epileptogenesis were investigated to identify differentially expressed circulating miRNA and isomiR profiles as biomarkers for epileptogenesis. Plasma samples were collected on day 2 and day 9 during the latency period from animals that did or did not develop epilepsy during the long-term video-electroencephalogram monitoring. MiRNAs and isomiRs were identified and measured in an unsupervised manner, using a genome-wide small RNA sequencing platform. ROC analysis was performed to determine the performance of putative biomarkers. Findings – Two days after an epileptogenic insult alterations in several plasma miRNAs and isomiRs predicted epileptogenesis in a model-specific manner. One miRNA, miR-3085, showed moderate sensitivity and specificity as a prognostic biomarker for epileptogenesis in all four models (AUC 0.729, sensitivity 83%, specificity 64%, p<0.05). Interpretation – Identified plasma miRNAs and isomiRs are mostly etiology-specific rather than common prognostic biomarkers of epileptogenesis. These data imply that in preclinical and clinical studies it may be necessary to identify specific biomarkers for different epilepsy etiologies. Importantly, circulating miRNAs like miR-3085 with high negative predictive value of epileptogenesis in different etiologies could be useful candidates for initial screening purposes of epileptogenesis risk Funding – This research was funded by a grant from the European Community (FP7- HEALTH project 602102 [EPITARGET]).