EPIMIRNA

"MicroRNAs in the Pathogenesis, Treatment and Prevention of Epilepsy"

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 Obiettivo del progetto (Objective)

'Epilepsy is a major burden for patients and health systems worldwide. It is a common chronic neurological disorder affecting people of all ages, and the shortfall in existing treatments means that 30% of patients continue to suffer uncontrolled seizures. MicroRNAs (miRNA) are a recently-discovered, network-level layer of gene expression regulation that controls protein levels of entire signaling pathways. Research on miRNAs has unprecedented potential to (i) further our understanding of the underlying disease processes, (ii) deliver novel signatures and prognostic markers for response to therapy, and (iii) deliver novel therapeutics and drug targets. EpiMiRNA consortium members have pioneered discoveries on brain-specific miRNAs, established that miRNA changes are a feature of the pathophysiology of human temporal lobe epilepsy and have demonstrated experimentally that altering miRNA function can potently suppress epileptic seizures and seizure-damage. EpiMiRNA brings together experts on the neurobiology of miRNAs with the leading researchers working on miRNAs in epilepsy, epilepsy geneticists, leaders in miRNA-target detection, proteomics, and systems biology with research-intensive SMEs pursuing miRNA therapeutics and treatments for pharmacoresistant epilepsy. Through highly collaborative, inter-disciplinary and inter-sectorial research, EpiMiRNA will explain the mechanism by which miRNAs contribute to epileptogenesis, characterize genetic variation of miRNA in patients, evaluate seizure-suppressing effects of miRNAs in experimental models, identify novel miRNA modulatory molecules as potential future therapeutics, and develop miRNAs as prognostic markers to identify patients who respond to novel, non-pharmacological therapeutic interventions including brain stimulation. EpiMiRNA will generate the necessary critical mass in biomedical, clinical and industry/SME research to track, treat and prevent seizures and improve the clinical management of epilepsy patients.'

Introduzione (Teaser)

In Europe alone, around six million people suffer from epilepsy. EU-funded researchers are working on elucidating epilepsy pathogenesis and developing novel and effective RNA-based therapeutic strategies.

Descrizione progetto (Article)

Recent breakthroughs in science reveal that microRNAs (miRNAs) affect brain cell structure as well as function. miRNAs are non-coding RNA molecules critical for network-level regulation of gene expression. Epilepsy is a neurological disorder characterised by recurring seizures that may be associated with changes to brain levels of specific miRNAs that not only can serve as diagnostic/ prognostic markers, but that are also prime targets for novel approaches to treat epileptic seizures.

Under the aegis of the 'MicroRNAs in the pathogenesis, treatment and prevention of epilepsy' (http://www.epimirna.eu (EPIMIRNA)) project, scientists are working on identifying miRNA that are altered during epilepsy development and determining their contribution to epilepsy pathogenesis. For this purpose, they analyse miRNA levels in brain tissue and biofluids from different animal models as well as from epilepsy patients.

This project has set up already a high-throughput miRNA biofluid profiling platform that is highly sensitive and shows good reproducibility. Necessary protocols, cell lines and reporter assays for validating results with candidate miRNAs have been established.

While only at an early stage, specific microRNA profiles that may serve as diagnostic markers and/or become therapeutic targets have already been identified, f.ex. miRNA-134 was found to be upregulated in people with epilepsy.

Small, chemically modified double-stranded RNAs that mimic endogenous miRNAs to selectively upregulate miRNA expression, were made and tested.

A smart diagnostic 'combi' device has been developed and is clinically being tested in the project that allows for intracortical EEG and microdialysis sampling (to monitor miRNA levels) at the same time.

After obtaining the requisite ethical approvals, patient recruitment and sample collection is ongoing to investigate variants in miRNA sequence in the genome of epilepsy patients.

In parallel, researchers developed a computational model of a hippocampal pyramidal neuron along with single cell imaging methods. This will prove useful in quantifying neuronal excitability during miRNA-mediated changes.

Project activities will help identify miRNAs linked to epilepsy and improve our knowledge about this serious and disabling brain disease. This should prove useful in developing effective diagnostic and therapeutic strategies. Successful outcomes will improve the prognosis for millions of patients with epilepsy while boosting the competitiveness of the European biomedical industry.