Community Research and Development Information Service - CORDIS

H2020

ECMED Report Summary

Project ID: 642881
Funded under: H2020-EU.1.3.1.

Periodic Reporting for period 1 - ECMED (The Extracellular Matrix in Epileptogenesis)

Reporting period: 2015-01-01 to 2016-12-31

Summary of the context and overall objectives of the project

"This project is aimed at finding new therapies for epilepsy. Although commonly regarded as a disease, epilepsy is more appropriately considered a symptom of brain dysfunction whether the cause is genetic or acquired. Indeed, there are multifarious aetiologies of epilepsy ranging from head injury and prolonged seizures to more general dysfunction such as dementia, including Alzheimer’s Disease. The development of epilepsy (epileptogenesis) is associated with many changes in the brain, and it is likely that targeting any one of these will not be effective - partly explaining why a variety of previously tried c treatment strategies have failed. Indeed, there has been no clinical study that has demonstrated successful modification of the severity or frequency of epilepsy following brain insults. Our present drugs treat the symptom, seizures, but do not modify the disease, epilepsy.
This project is aimed at addressing this treatment gap, and proposes a completely novel treatment and diagnostic approach.
Conventional approaches to study epilepsy have concentrated on neurotransmitters, channels and receptors, and the modifications that can occur to these during the development of epilepsy (epileptogenesis). There is burgeoning evidence that extracellular proteins that form the extracellular matrix (ECM) play a fundamental role in neural development and regeneration, synaptic plasticity, neuronal excitability and network activity – key players in epilepsy.

Epilepsy carries an enormous burden to the individual and to society. It is the commonest serious neurological condition, and the most ubiquitous, affecting people of all ages and social classes. At least 60 million people worldwide (6 million people in Europe) have epilepsy, and over a third of people with epilepsy do not respond to our present treatments. Epilepsy is associated with under- and un-employment, depression, anxiety, poorer general health, and increased mortality rates. It therefore has a tremendous impact on the individual and also on society – the estimated total cost of epilepsy in Europe in 2010 was €13.8 billion. Nothing has been shown to modify the prognosis of epilepsy; this project addresses this need.

This project aims (i) to understand the key mechanisms of epileptogenesis mediated by changes in the extracellular matrix, (ii) to detect and prevent changes in the ECM during the development of epilepsy, and (iii) to develop ECM-targeting treatment strategies that enable the ""correction"" of abnormal brain circuits that underlie epilepsy."

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

This work of project has two main aims: first to undertake the research project and second to train and support early stage researchers.

For each early research researcher (ESR), a Career Development Plan has been set out, tailored to the individual needs of the trainee and in relation to the research project. A ‘Career Development Plan Template’ has been agreed upon. All ESRs have registered for a Ph.D. program with their local University. Hands-on training has involved close interactions with their supervisor and with postdoctoral fellows, other Ph.D. students and technical staff in their local institute. The ESRs have carried out 3 workshops (Analysis of neuro-dynamics using microelectrode arrays in vitro and in vivo, Virus-mediated gene-delivery into the rodent brain and Strategies to transport CNS drugs across the BBB & biotechnology entrepreneurship) and two advanced training courses (Understanding epilepsy and The (peri)synaptic ECM: implications for neural development & synaptic plasticity). A website has been established and ESRs have been involved in presentations and outreach activities.

In the research project the following work has been carried out and results achieved:
1) Research on biomarkers of epileptogenesis (biological indicators of the development of epilepsy). We have carried out work on human and rat tissue that has identified microRNAs (small RNA that regulate gene expression) that regulate extracellular matrix proteins and the expression of which are altered during the development of epilepsy. We have also determined the brain and blood concentrations of some the extracellular matrix components during the development of epilepsy. Lastly, we have used ligands that target the extracellular matrix as potential imaging tools to determine if we can use brain scans to follow the development of epilepsy.
2) Research on anti-epileptogenic treatments. We have developed in vitro tools that avoid aims use in order to gain insights into changes that occur in the extracellular matrix during epilepsy and what effect targeting the extracellular matrix has on epileptic activity and the development of epileptic activity. We have also characterised mouse models in order to gain a better insight into the role of the extracellular matrix in brain disease.
3) Research on anti-epileptic treatments, The aim of this part of the work is to determine if we can halt epilepsy once it has become established. We have joined a neuropeptide that does not normally cross for blood into brain with a vector to increase its transport into the brain, across the blood brain barrier.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The progress beyond the state of the art has occurred on three fronts;
First, the establishment of potential biomarkers for the development of epilepsy and disruption to the extracellular matrix.
Second; a greater understanding of the role of the extracellular matrix in regulating network activity
Third: potential treatments targeted at the extracellular matrix that could have an impact on established epilepsy or could prevent the development of epilepsy.

The potential impact of the project has occurred in three fronts:
First, the training and education of early career researchers. This is not only important for European science but also by directing these researcher translational neuroscience, we have actively promoted the interaction between ESRs and clinicians in order to give them a better insight into the questions and strategies important for ultimately improving health care.
Second, the interaction with SMEIs promotes a dialogue between scientists and industry that will facilitate the translation of new discoveries into commercially viable products that could enter the clinical arena.
Third, developing new strategies to treat epilepsy. Epilepsy is a major health burden throughout Europe and the treatments that we have target the symptom and not the disease. This project concentrates on three main paths to impact. The first basic-and-clinical research-oriented path is the identification of biomarkers that will predict who will develop epilepsy after an insult. This is critical since even after a severe traumatic brain injury only about 20% will develop epilepsy. The identification of biomarkers will provide essential tools to maximise the power of human trials in epilepsy. Moreover, such biomarkers will permit targeted treatments. The second applied and intersecting path is the development of treatment strategies to prevent the development of epilepsy in these at-risk patients and the third, also applied and intersecting, path is the development of treatment strategies (disease-modification and cure) for patients with established epilepsy.

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