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EPIMIRNA Report Summary

Project ID: 602130
Funded under: FP7-HEALTH
Country: Ireland

Periodic Report Summary 3 - EPIMIRNA (MicroRNAs in the Pathogenesis, Treatment and Prevention of Epilepsy)

Project Context and Objectives:
There are 6 million people with active epilepsy in Europe. Temporal lobe epilepsy (TLE) is the most common and intractable form in adults and is often acquired as a result of insults to the brain. Better treatment and prevention requires understanding the epileptogenic process. MicroRNA (miRNA) is an important class of non-coding RNA that is critical for network-level regulation of gene expression and is likely to play an important role in driving the concerted changes to gene expression that are a feature of the epileptogenic process. Work to date has identified a few miRNAs that influence the pathogenesis of epilepsy by regulating neuronal structure and excitability, gliosis, inflammation and apoptosis. Targeting miRNAs may therefore represent a novel approach to anti-epileptogenesis. Genetic variation in miRNA sequences may also contribute to disease risk and miRNAs in biofluids may represent novel diagnostic biomarkers.
The objectives of the EpimiRNA project are to:
(a) explain how miRNAs and their protein targets contribute to development of epilepsy and triggering of seizures
(b) identify miRNAs that are biomarkers of epileptogenesis or seizures and use miRNA profiles to improve medical devices for treatment-resistant seizures in patients
(c) identify genetic variation in miRNAs in epilepsy patients
(d) develop novel miRNA-based treatments that can prevent TLE development or halt seizures in established epilepsy.
To achieve these objectives EpimiRNA has teams of experts in pre-clinical and clinical epilepsy research and specialists in miRNA biology, RNA silencing, quantitative proteomics, systems biology, drug delivery and gene therapy. These are complemented by SMEs developing miRNA therapeutics, diagnostics and devices for the treatment of epilepsy, and data analytics. The project comprises a series of 11 workpackages.
WP1 will characterize miRNAs in brain and biofluids from three different animal models at partners 01 RCSI, 02 UNIMAR and 05 UNIVR to identify the miRNA changes that occur during epileptogenesis. WP2 is led by 06 UKER and will characterize the miRNA profiles in brain tissue from epilepsy patients and miRNA levels in biofluids before and after seizures in patients. This WP will also develop a new combined intracortical EEG-microelectrode with 11 Dixi. WP3 will define miRNA changes following experimental brain stimulation as well as determine whether brain stimulation in patients or volunteers produces a miRNA signature that can be used as a biomarker. WP4 led by 03 UMCU will identify the gene targets of the identified miRNAs and assess the impact of manipulating these miRNAs on animal behavior and brain excitability. WP5 is led by 17 CU (formerly 07 Duke) and will determine the genetic variation in miRNAs, their biogenesis enzymes and in the 3’ untranslated regions of hippocampal genes (a total of ~90,000 targets) in 1600 patients and controls. WP6 is led by 09 AU and with SME BCPlatforms will develop an integrated data storage and retrieval platform to handle the miRNA brain and biofluid datasets, genetics and proteomics data. This will then be a resource for data mining, hypothesis testing and biomarker identification. WP7 will develop computational models that can predict effects of epilepsy-associated miRNA expression changes on network excitability which will be fed back to in vitro and in vivo testing and biomarker prediction. WP8 Is led by 04 UCL and will perform in vivo manipulations of miRNAs and assess the impact on epileptogenesis in animal models. WP9 will develop in vitro screening assays to profile partner 14 Bicoll’s unique chemical library to identify natural compounds that display miRNA inhibitory properties that could be developed for anti-seizure or disease-modifying effects. WP10 features dissemination of EpimiRNA activities, training and exploitation of discoveries. Finally, WP11 is project management and is led by 18 ARTTIC.

Project Results:
WP1 Production of brain tissue samples from the three animal models of epilepsy has been completed and hippocampal miRNA sequencing has been completed; miRNAs common-to-all three models were identified at different stages of epilepsy development. For two of the three models, all blood samples have been generated and miRNA analysis completed. WP2 Patient recruitment at clinical sites has been very successful with blood samples collected from over 300 controls and patients during video-EEG monitoring and at out-patient clinics. High-throughput qPCR analysis and RNA sequencing of miRNA in blood is completed. We have a substantial collection of CSF samples from TLE and status epilepticus patients and miRNA analysis performed that has identified miRNA unique to both conditions. A collection of hippocampal samples from TLE patients after neurosurgery is complete. A prototype of the device for combined intracortical EEG depth-electrode and microdialysis was manufactured and clinical trial planning progressed. WP3 Production of brain tissue is completed for the rat model of epileptic tolerance and all brain samples have been processed for miRNA sequencing which has identified a number of miRNAs showing differential responses. Different brain stimulation protocols have been trialed in rats and evidence of a new “protective” stimulation site found. The tVNS clinical trial began. WP4 miRNA-target analysis identification efforts progresses well with quantitative proteomic analysis of miRNA effects in cells undertaken. Targets of novel epilepsy-associated miRNAs were identified and the cell phenotypes expressing these miRNAs were identified using in situ hybridization and cell-based assays. WP5 DNA sample number targets were achieved for this WP with >850 TLE+HS and over 1000 sporadic (other) epilepsy samples in place, as well as over 1700 controls. Sequencing is nearly complete for all controls and patient samples. WP6 RNA sequencing analysis of all animal model brain samples is completed. Results show outstanding depth and quality of data. Work to establish the iCLIP procedure for brain tissue continued and BC Platforms has populated the EpimiRNA server with numerous annotated data from sequencing and biomarker datasets. An epilepsy-miRNA open-access database was established. WP7 Systems biology computational modelling of miRNA and their targets has been successful for a single hippocampal pyramidal neuron model validated by electrophysiology. Interaction maps for key miRNAs identified by the consortium have provided testable predictions about which of the novel miRNAs will produce seizure phenotypes when targeted and several have been validated experimentally. WP8 This WP made strong progress, including systematic in vivo functional assessments of antagomirs targeting novel miRNAs. Seizure phenotypes were identified for approximately half of those tested. New techniques for delivering antagomirs were developed and validated. We also extended evidence of disease-modifying effects of Ant-134 to the rat perforant path model. WP9 Work on the miRNA-based medium-high throughput cell assay continued with further screening of the compound library assembled by Bicoll. Neuroprotective compounds were also identified using a second cell-based assay. WP10 We published papers on the miRNA database ( in Bioinformatics, a review on miRNA in Epilepsia and original research in Scientific Reports on miR-22 in epilepsy and circulating miRNAs in plasma (PLoS ONE, RSC Adv). The EpimiRNA website and social media use increased including a Twitter account (@Epilepsylab) which has many followers. WP leaders organized workshops at the IEC conference and at the final EpiExchange network meeting that featured also the coordinators of EpimiRNA, EpiTarget, EpiSTOP and Desire.

Potential Impact:
The expected final results of the EpimiRNA consortium are the following:
(1) Identification of novel miRNAs in epilepsy. Our research is generating the most complete characterisation of functioning miRNA responses in experimental and human epilepsy and is now complete for three animal model across all stages of epilepsy development. This is a major step toward a comprehensive knowledge of how miRNAs control gene expression in epilepsy. The data also drives novel directions in pre-clinical anti-epileptogenesis strategies.
(2) Deep mechanistic understanding of how miRNA changes de-stabilize neuronal networks in brain. Our studies are identifying novel miRNAs that control genes regulating brain excitability. By locating these miRNA within causal pathways our results will explain how miRNA changes influence the epileptogenic process and lead to lasting changes in brain excitability.
(3) Identification of molecular biomarkers of epilepsy. We are identifying miRNAs in biofluids such as blood that discriminate TLE patients from controls and other neurological disorders that could help predict disease risk and course/prognosis, direct treatment and avoid adverse side-effects, thereby revolutionising care of epilepsy patients. miRNA biomarkers of non-pharmacological treatments (e.g. brain stimulation) will improve use parameters to help patients better control their seizures with fewer side effects. We expect to create new IP and pursue commercialisation toward licensing or a small diagnostic-based spin-off/start-up company and we develop new assays for direct, non-amplified detection of epilepsy-associated miRNA in plasma.
(4) Therapeutic targeting of novel miRNAs. We are generating an extensive dataset on seizure phenotypes from antagomir screening of novel miRNAs and other approaches in rodent models. These results will drive interest within (e.g. InteRNA, Bicoll) and outside the consortium (e.g. Biotechnology companies working in RNA therapeutics), as well as academic teams, and stimulate future therapeutic approaches to prevent the development of epilepsy.
(5) Identification of miRNA genetic variants in patients. DNA sequencing of miRNA will define a new area of human epilepsy genetics that improves our understanding of epilepsy, can lead to revised standards that potentially reduce time to diagnosis and treatment. This provides potential healthcare savings and refines genetic counselling so patients have a better understanding of the cause and prognosis of their condition.
(6) Technological advances. Technological advances and training will be delivered from adapting techniques to characterise miRNAs with small RNAseq, as well as generating a systems biology framework for miRNA. EpimiRNA will deliver advances in gene therapy, oligo/DNA-based and traditional small chemical scaffolds. EpimiRNA will generate databases and a new data integration platform for RNA-seq, genetics and proteomics.
SME impact: EpimiRNA will afford SME partners several opportunities to develop and protect intellectual property rights (IPR) in the areas of therapeutics, medical devices for epilepsy, miRNA tools and data platforms.
Stakeholder impacts: The programme satisfies demands for more research into epilepsy from patient groups and research agendas. In its third year EpimiRNA-associated partners participated in a range of scientific and lay-audience activities to promote epimiRNA and published a number of scientific reviews and original articles. Our programme will ensure continued engagement and agenda sharing with stakeholders to ensure an engaged and scientifically informed public.
Other impacts: The programme creates new inter-sectorial collaboration that increases the quality of scientific research, drives innovation and ensures translation. The high-impact science of EpimiRNA will support researchers becoming competitive for funding under other European programmes (e.g. ERC).

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