The Network

Objectives & Impact


Introduction to the challenge

Epilepsy carries an enormous burden to the individual and to society. Epilepsy 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. It has a tremendous impact not only to the individual but also to society – the estimated total cost of epilepsy in Europe in 2010 was €13.8 billion.

Although commonly regarded as a disease, epilepsy is more appropriately considered a symptom of brain dysfunction whether the aetiology is genetic or acquired. Indeed, there are multifarious aetiologies of epilepsy ranging from specific brain insults such as head injury and prolonged seizures to more general dysfunction such as dementia, including Alzheimer’s Disease, and inflammatory diseases. The development of epilepsy (epileptogenesis) is associated with a multitude of changes in ion channels, receptors, synapses and network connectivity. It is likely that there is considerable redundancy in the epileptogenic process, so that targeting any one of these will not be effective - partly explaining why a variety of previously tried antiepileptogenic treatment strategies have failed. Indeed, there has been no clinical study that has demonstrated successful modification of the severity or frequency of epilepsy following such insults. ECMED is aimed at this treatment gap, and thus proposes a completely novel treatment and diagnostic approach. ECMED will also be relevant to epilepsy secondary to genetic conditions that disrupt or result from disruption of extracellular matrix (ECM). 

Conventional approaches to studying 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 ECM proteins play a fundamental role in neural development and regeneration, synaptic plasticity, neuronal excitability and network activity – key players in the pathogenesis of epilepsy.  Evidence that supports this includes:

  1. the emerging role of ECM in brain diseases associated with epilepsy such as stroke, neurodegeneration, schizophrenia and autism; 
  2. the association between ECM protein mutations and epilepsy; and 
  3. the contribution of ECM to acquired epilepsy through changes in the synaptic plasticity machinery.

Molecule

Scientific Aims

  • to understand the key mechanisms of epileptogenesis mediated by activity dependent remodelling of extracellular matrix
  • to detect and prevent changes in the ECM during early epileptogenesis
  • to develop ECM-targeting treatment strategies for “opening a window” for persistent structural normalisation of neural circuitries in late stages of epileptogenesis as well as in established epilepsy.

Project Objectives

  • to understand remodelling of ECM during epileptogenesis, 
  • to identify ECM components or their degradation products that can serve as biomarkers for early diagnostics of epileptogenesis, 
  • to identify targets for prevention of epilepsy-related ECM alterations, 
  • to identify targets prompting restoration of neural connectivity during established epilepsy,
  • to validate biomarkers and treatment targets in pre-clinical animal models.

Innovative aspects of the research programme

Epilepsy treatment has conventionally been symptomatic in which “antiepileptic drugs” treat the symptom, seizures, but not he underlying disease, and so would be better termed “antiseizure drugs”. There is, therefore a great unmet need for treatments that modify the disease, especially in acquired drug-resistant epilepsies. 

Exploring the ECM as a potential therapeutic target for the treatment of epilepsy is a completely novel strategy, which demonstrably goes beyond the current state of the art in experimental and translational epilepsy research. This strategy builds upon several significant advances in molecular signalling mechanisms that suggest an active role for the ECM in the regulation of neuroplasticity and neural network activity. 

The ECM plays a critical role in governing brain excitability and function, and our understanding of its physiological importance has burgeoned in recent years. Despite this, there is a paucity of studies of ECM in epilepsy, even though there are many advantages of targeting ECM in the context of epilepsy: we know that genetic modification of ECM proteins induce or modulate epileptogenesis and thus the ECM is a legitimate target for anti-epileptogenic treatments; ECM molecules form stable scaffolds stabilising cell-cell contacts and the cytoskeleton, so regulating the formation and stability of neuronal networks; ECM molecules regulate expression and function of receptors and ion channels involved in synaptic activity, providing a strategy to target functional homeostasis in the brain; the ECM is more easily accessible to drugs than intracellular targets; and ECM components in the cerebrospinal fluid (CSF) and serum change under various pathologies, which could provide a powerful biomarker and thus diagnostic tool of early epileptogenesis.

Many of the fundamental discoveries of the role of the ECM in neuronal signalling and network function have been through studies performed in the laboratories of members of this consortium. This project sets out to exploit this expertise and to realize the translational potential of these crucial findings in epilepsy.


Expected Results and Impact

ECMED is planned in such a way that expertise in the basic science of ECM is translated to pre-clinical settings, enabling eventual translation to human therapies. 

The consortium draws upon considerable multidisciplinary expertise across Europe from a wide-range of research areas including neuroimaging, electrophysiology, histopathology, molecular neuroscience and pharmacology, and thus provides an excellent interdisciplinary training network for Early Stage Researchers (ESRs). Together with the strong industrial partners to exploit this knowledge for the development of innovative approaches to prevent and “cure” epileptic disorders. The consortium is so designed that discoveries from academia are directly communicated to industrial partners in order to develop novel therapeutics, which can then be tested by the academic partners. This strong bidirectional interaction again provides a rare and advantageous training network approach. 

Moreover, one of the failings in epilepsy research is that much of it has been associational; the changes that occur in channels, synapses, circuits and networks with epileptogenesis have been carefully dissected but the causal relationship has rarely been clearly demonstrated. It is only through establishing that an intervention that directly remedies these changes has an impact on epilepsy and/or epileptogenesis that a causal role can be established. Therefore the development of novel treatment strategies in ECMED will not only have translational potential but also will substantiate the link between observed changes and epileptogenesis, enabling the further development of therapies.

Beyond this, this network is designed to train scientists of the future. It has been increasingly important for all biomedical research to have a translational component, enabling even the most basic research to contribute to the health of society. We have set out to create a research and training programme that combines exposure to state-of-the-art methods in biological research with translational components and, importantly, an understanding of the human impact. Although there is a considerable medical need for research in epilepsy, epilepsy is also a prototypical disease for translational research, combining a fundamental understanding of mechanisms that regulate neuronal and network excitability in the brain with an important translational aspect. 

The inclusion of two companies that are concerned with the translation of fundamental research into drug discovery is a critical part of this. We have also included training in "understanding the clinical problem" in which ESRs will be exposed to information from not only clinicians but also patients, patients' families and epilepsy charities. We have found that giving researchers a context to their research improves considerably both their experience and also their understanding of the problems that need to be addressed. Within this, we will also give the researchers an opportunity to be involved in public engagement.

Lastly, ECMED appreciates that the career paths of early career researchers can be quite diverse, including teaching, research, work in industry, medical writing and administration. Our research and training programme addresses these needs.

Page last modified on 02 mar 17 17:32