The future of epilepsy research: new personalised treatment options and novel therapeutics.

It is estimated that the first human genome sequenced in 2003 cost almost $1 billion and took four years to complete. Fast-forward fifteen years, and remarkably, genomic technologies have advanced so quickly that DNA sequencing is now a valuable and cost-effective clinical tool. The field of epilepsy research has certainly benefitted from genomics, providing a rapid advance in our understanding of the genetics of these disorders. Approximately one third of all epilepsies are estimated to have a genetic cause, and DNA sequencing of families has identified many new genes that are likely to be disrupted in certain forms of the disease. Furthermore, in cases where an unidentified epilepsy syndrome is presented, sequencing the protein-coding proportion of the genome (exome sequencing) has become an important way of identifying the best individual treatment strategy. We are now in an exciting era where these types of data can be considered by experienced medical professionals alongside other factors such as lifestyle and environment, defining a new ‘precision medicine’ approach to treatment.

Examples of anti-epileptic treatments being selected – or importantly, specifically avoided – based on DNA sequence are still rare. For example, deficiency for a protein that helps transport glucose to the brain from the blood (GLUT-1) causes a rare genetic syndrome that can result in severe epileptic encephalopathy. Knowledge of the biochemistry of GLUT-1 function means that a change in diet, so that the brain can use a different form of energy to replace the missing glucose, has proven to be highly effective. Such personalised treatment and prevention strategies will undoubtedly become more prevalent over the next 10 years. In addition, specific changes in a protein identified by genomic sequencing have the potential to be modelled by computer simulations or laboratory experiments within in a matter of weeks, and these data may be crucial for determining the best treatment. Taking this genomic approach even further, the sequence of an individual may provide clues as to additional variations in their DNA that might influence the choice of treatment, even the way a drug may be metabolised in the body. This highly detailed, personalised ‘pharmacogenomics’ strategy is still very new, therefore considerably more research is required in the coming years for this exciting approach to be more widely adopted in the clinic.

Epilepsies form a large and complex group of disorders; yet there is increasing evidence that certain classes of the disease may converge of a small set of key molecular mechanisms. Consequently, as more genetic causes of epilepsy are discovered – even very rare or unique forms – the power of these data will in part come from the identification of overlapping pathways in the brain that could be targeted by novel therapeutics. By understanding the fundamental biology that underlies the regulation of these pathways, we will be able to discover new ways to modify them that will be beneficial to a wide range of epilepsies. For example, our own work recently funded by ERUK is focussing on one such pathway that is essential to the way brain cells communicate with one another. Specifically, we are investigating the gene TBC1D24, one of the first epilepsy genes to be discovered by exome sequencing in 2010. Since that time, many more patients presenting with epilepsy worldwide have been found to have mutations in TBC1D24. Using this new and expanding clinical dataset, we can quantify how communication between neuronal cells is disrupted when the same parts of the TBC1D24 protein are changed in model systems; our new findings show that this gene is involved in pathways shared with multiple epilepsy syndromes.

In summary, this is an exciting time for epilepsy research, with genomic data becoming an ever-more important aspect of research and clinical practice. In the coming years, we will gain an increased understanding of large and complex genomic datasets from multiple patient groups; importantly, this must be combined with basic biological investigations, the experience of epilepsy clinicians and effective genetic counselling. With such a multi-disciplinary approach, the future is bright for new personalised treatment options and the longer-term discovery of novel therapeutics for epilepsy.

With many thanks to Associate Professor Peter Oliver, MRC Harwell Institute for this opinion piece.

 

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