EU - FP7 - MicroRNAs in the Pathogenesis, Treatment and Prevention of Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurring, unprovoked seizures. There are 6 million people with active epilepsy in Europe, with poor seizure control accounting for most of the socio-economic burden of the disease. Temporal lobe epilepsy is the most common syndrome in adults and is also the most prone to pharmacoresistance. We still lack a complete understanding of the epileptogenic process. Equally, the population of refractory patients has remained stubbornly fixed at ~30% despite new anti-epileptic drugs (AEDs). New thinking about the mechanism of epileptogenesis and the treatment and prevention of TLE is needed. Indeed, evidence is emerging that epilepsy and epileptogenesis are controlled by epigenetic factors and gene products that control multiple genes and proteins systematically/on a systems level. This new evidence is the major challenge and opportunity which this consortium intends to address at a European level. MicroRNA (miRNA) is an important class of non-coding RNA that is critical for network-level regulation of gene expression, and because it can repress or fine-tune protein output from cohorts of genes miRNA is ideally placed to drive the concerted changes that occur during epileptogenesis. Recent breakthrough discoveries revealed that miRNAs contribute extensively to the pathogenesis of epilepsy: during epileptogenesis, miRNAs regulate neuronal structure and excitability, gliosis, inflammation and apoptosis. Animal studies show that targeting miRNAs can potently inhibit the development of seizures after an epileptogenic insult. Advances in nucleic acid chemistry have generated stable locked nucleic acid-modified oligonucleotides (“antagomirs”) for use as miRNA therapeutics. Due to its stability and multi-targeting, miRNA also has unprecedented potential as a future treatment of human disease. EpiMiRNA partners are the leaders in research into miRNA in epilepsy, which has the potential to transform our knowledge of the pathogenesis of epilepsy, improve our understanding of the mechanisms and the failure of current treatments including AEDs, and to develop new sets of drug targets. Pioneering contributions from EpiMiRNA partners include identification of a brain-specific miRNA controlling neuronal microstructure and excitatory synaptic transmission, the first in vivo tests to show miRNA inhibitors can prevent epileptic seizures and hippocampal damage in mice, and the first global analysis of miRNA in human epilepsy. The consortium has a very novel approach, with experts in pre-clinical and clinical epilepsy research, human genomics, small RNA delivery, miRNA sequencing & quantitative proteomics, and systems biology to mathematically model the pathways. The EpiMiRNA consortium is complemented by research-active SMEs developing miRNA therapeutics (InteRNA), and analytics, diagnostics and devices for the treatment of epilepsy (Dixi, Cerbomed, Bicoll, BCPlatforms). Devices for non-pharmacological treatment of epilepsy – brain stimulation techniques including vagus nerve and deep brain stimulation (VNS, DBS) – have become of increasing clinical importance, yet lack of understanding of their mechanisms of action limits our knowledge of which patients benefit from their use. EpiMiRNA’s overarching goals are to track miRNA changes after seizures (including in humans), and in response to treatment, explain how miRNA influences epileptogenesis and ictogenesis, investigate genetic variants in TLE patients to explain aetiology and their response to treatment, and use this to establish miRNAbased therapeutics to track, treat and prevent epilepsy.