Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ECMED (The Extracellular Matrix in Epileptogenesis)

Teaser

What is the problem?Epilepsy affects about 1% of the population; approximately 6 million people in the EU have epilepsy with an incidence of about 300,000 new cases per year. In Europe alone, approximately 2 million (0.3% of the population), continue to have seizures despite...

Summary

What is the problem?
Epilepsy affects about 1% of the population; approximately 6 million people in the EU have epilepsy with an incidence of about 300,000 new cases per year. In Europe alone, approximately 2 million (0.3% of the population), continue to have seizures despite optimal medical treatment.
Unfortunately, new drugs for epilepsy have had little impact on this group, and so new targets and approaches for drug development are needed. Moreover, many people develop epilepsy following a brain insult such as a head injury, stroke or prolonged seizure (status epilepticus), yet none of our present treatments either prevent the development of epilepsy or modify the prognosis of epilepsy.
As our understanding of the brain has advanced, it has become increasingly apparent that the proteins that surround nerve cells - the extracellular matrix (ECM) - are not only important for maintaining the structural integrity of the brain as a sort of “scaffold” but play key roles in regulating the excitability of the brain and the way that nerve cells behave.
Some genetic epilepsies are caused by mutations in genes that encode ECM-related proteins, yet the effects and impact of these mutations are not fully understood. Also, the way that the ECM changes during the development of epilepsy following a brain insult and the role that these changes play in epilepsy remain unknown. Moreover, drugs and other therapeutic approaches that target the ECM could provide a completely new way to treat epilepsy and to prevent or modify the condition.

Why is it important for society?
Epilepsy is one of the commonest serious neurological conditions. Patients with drug resistant epilepsy have a yearly mortality of 0.5-1% due to sudden unexpected death in epilepsy (SUDEP) which mostly affects young adults. In addition, drug resistant epilepsy is associated with high rates of depression, suicide, accidents, and social exclusion. In 2010, the estimated cost of epilepsy per year in the EU was €14 billion, most of which was attributed to indirect costs such as under-and unemployment, and most of which is due to drug resistant epilepsy. Providing novel therapies to treat and prevent epilepsy could, therefore, have a substantial societal impact. Beyond this, a greater understanding of how the ECM regulates brain excitability and therapies that target ECM-related proteins may have relevance to many other neurological conditions such as dementia, stroke and head injury.

What are the overall objectives?
The overarching objective of this project is to understand the part that change in the ECM play in the development and maintenance of epilepsy and to determine ways to target the ECM to treat epilepsy. Within this, we had specific objectives (i) to understand how the ECM changes during the development of epilepsy (epileptogenesis), (ii) to identify ECM-related components that can serve as biomarkers to predict those who will develop epilepsy, (iii) to identify targets for prevention of epilepsy-related ECM alterations, (iv) to identify targets that can help treat established epilepsy, and (v) to undertake preclinical testing of these biomarkers and treatments in order to facilitate eventual translation to the clinic.
A further important objective was the scientific training and education of early-stage researchers (ESRs) across Europe in order to enrich the European scientific community.

Work performed

Within the objectives of the project, there were 12 specific projects carried out by early-stage researchers (ESRs) in 9 European countries spanning the continent.
The work carried out by these ESRs comprised detailed examination of the impact of epilepsy or traumatic brain injury on specific proteins of the extracellular matrix, determination of brain and blood biomarkers that can help predict the development of epilepsy, establishing novel ways of testing therapies that may reduce and replace in vivo animal testing, and development of therapies that target the extracellular matrix to treat and/or prevent epilepsy.
There are a number of major results that have been or are in the process of being published in peer-reviewed journals. These have included: i) loss and disruption of specific ECM proteins during the development of epilepsy including perineuronal nets, brevicans, LGI1 and integrans and the demonstration that these observed changes have a crucial impact on neuronal and network excitability, and so contribute to the epileptogenic process; ii) changes in miRNA expression and specific ECM-related proteins in brain and plasma following prolonged seizures and traumatic brain injury in preclinical models that have the potential to be markers of brain injury and the development of epilepsy; iii) the development of new ligands for PET scanning that may facilitate the development of imaging biomarkers and iv) the development of a new drug that acts as an MMP-9 inhibitor with preliminary preclinical data indicating that this is a potential novel therapy to prevent the development of epilepsy.

Final results

For over a century, the treatment of epilepsy has focussed on the use of drugs that target receptors and channels on nerve cells, which dampen down excitability and reduce seizure frequency. These treatments have not been shown to modify the prognosis of epilepsy or to prevent epilepsy following a brain insult (epileptogenesis). As a consequence, various strategies to prevent epileptogensis have been explored with mixed results including targeting inflammation, reaction oxygen species, growth factors, phosphorylated tau and the mTor pathway.

Exploring the ECM as a potential therapeutic target for the treatment of epilepsy demonstrably goes beyond the current state of the art in experimental and translational epilepsy research.
This strategy has built upon several significant advances in molecular signalling mechanisms that had suggested an active role for the ECM in the regulation of neural network activity and brain excitability. The findings from this project now clearly provide evidence for a role of the extracellular matrix in epileptogenesis and the generation of seizures. This now provides a completely novel strategy for the treatment and prevention of epilepsy with the hope that future translation into therapies will address a large unmet clinical need.

The project has also resulted in the training of early-stage researchers in translational research and has provided them with the tools to establish a career in science. Many have continued to work in their host laboratories and have submitted or are soon to submit their PhD theses, so promoting and supporting scientific training in the EU.

Website & more info

More info: http://www.ecmed-itn.eu.