Finding treatments for drug-resistant epilepsy: a novel drug discovery approach based on diverse model organisms.

Epilepsy is a common neurological disorder affecting ~1% of the population. Antiepileptic drugs are the mainstay of therapy but are ineffective in ~35% of people with epilepsy and are often associated with significant adverse effects. In addition to frequent seizures, people with uncontrolled epilepsy experience poor quality of life, cognitive decline, social stigma and elevated mortality; this represents a major unmet clinical need. Recent drug development for epilepsy has failed to produce new compounds that are significantly better than existing agents in terms of efficacy, tolerability or safety. This may be partly explained by failure to develop drugs that target the underlying disease process. Recent advances in the genomics of epilepsy now make that a more realistic possibility. This application brings together scientists with expertise in traditional rodent models of epilepsy (Sills) and in non-mammalian C. elegans worm (Morgan) and zebrafish (Cunliffe) models. We aim to establish a new paradigm for drug discovery in epilepsy, with simple genetically-tractable models systems at its core, allowing identification of compounds with activity under specific pathogenic conditions, and with validation provided by rodent models. To this end, we will use both C. elegans genetic models of seizures and a zebrafish chemical-induced seizure model to screen a library of compounds for anticonvulsant activity. Promising compounds will be validated in rodent models of both acute seizures and chronic epilepsy and then will be further characterised using genetic approaches to gain insight into molecular mechanisms of action of these novel compounds. The absence of voltage-gated sodium channels and the ability to genetically disrupt other common targets of current antiepileptic drugs in C. elegans increases the likelihood that this approach can identify compounds with novel mechanisms of action of potential use in pharmacoresistant epilepsy. As a proof of principle for our proposed collaborative approach, an unpublished zebrafish screen performed by Cunliffe at Sheffield has identified a novel compound that we have shown in Liverpool to also have anticonvulsant activity in C. elegans, with a potential receptor agonist mechanism of action deduced. Clearly, if we find such compounds to also be active in traditional rodent epilepsy models, these would be attractive candidates for novel therapeutics. The involvement of clinical epileptologists (Marson) in this project and our links to the pharmaceutical industry add genuine translational potential to the proposed research. This project will provide unique research training, as the student would gain in vivo expertise using three of the main model organisms used in biology and medicine. The student would also benefit from interaction with four highly experienced supervisors with complementary genetic, neurobiological, pharmacological and clinical expertise. Overall, this interdisciplinary project using diverse approaches will build much needed capacity in whole organism in vivo techniques and has the potential to make an impact on the significant clinical unmet need of pharmacoresistant epilepsy, which currently affects around 200,000 people in the UK.