What’s new and exciting in epilepsy research?
We asked Dr Robert Wykes, a translational medicine scientist for his personal perspective. Here is his response:
Despite decades of new anti-epileptic drugs (AEDs) reaching market, the problem of drug refractory epilepsy remains. 25-30% of patients do not respond appropriately to AEDs. However in recent years advances in technology and non-pharmacological approaches are beginning to address this clinical need. We are beginning to see the translation of these therapies with exciting and promising results. I suspect within a decade, real progress will be made in treating or even curing the 25-30% who currently have few, often palliative options.
For some drug refractory patients surgery may be an option, but its success is dependent on precise localisation of a seizure onset zone. Improvements in neuroimaging and the electrophysiological devices used to detect seizure onset zones are increasing the accuracy of the area of the brain targeted for resection. There is also a realisation that many focal onset epilepsies may have a more distributed epileptic network. Mathematical modelling and application of advanced fMRI-EEG studies are identifying distributed epileptic networks. Further understanding of the importance of these networks may be key to improving surgical outcomes.
Surgery though is only an option for a minority of drug refractory patients. For those unsuitable for surgery promising and exciting results have been reported particularly in childhood epilepsies treated with cannabinoids (you can find out more about the ERUK position on medicinal cannabis here:) or components of the ketogenic diet such as decanoic acid. Further basic science investigations into the mechanism by which these compounds work may lead to molecules with improved anti-seizure properties. Antagomirs, molecules that block specific microRNAs upregulated in epileptic brain, have also shown considerable preclinical efficacy and are likely to enter clinical trials in the not too distant future.
Gene therapy holds promise, as this allows the ability to design strategies to achieve region-specific and cell-specific modification of neuronal and circuit excitability. The viral vectors that are used to deliver transgenes are increasingly reliable in terms of expressing the transgene, and data on long-term safety are accumulating from other neurological diseases. The potential to translate gene therapy research to human pharmacoresistant epilepsy is not straightforward. However a decade of preclinical proof or principle basic science has resulted in at least two gene therapy strategies currently being funded for first in human studies. It is envisioned that the first people to receive a gene therapy treatment for epilepsy could be within the next 18 months.
Recent advances in gene-editing technologies such as the CRISPR-Cas9 system could in the future result in entirely novel treatment for epilepsy by repairing disease-causing gene mutations. Although this technology offers the prospect of a ‘cure’ and can be applied to neurones in a petri dish, there are significant advances still required before this technology enters clinical translation for epilepsy.
I believe the biggest breakthrough will come however from basic science. It is astonishing to realize that we still don’t know how a seizure starts or how it stops! Recent advances that allow imaging of neuronal activity in awake rodents, coupled with the development of sophisticated multi-electrode devices and in combination with molecular techniques to target distinct types of neurons are shining a light on these fundamental questions. Further work in this area will result in a better understanding of seizure initiation and termination which may result in a radically different approach to treat people with epilepsy.
With many thanks to Dr Robert Wykes, University College London, Queen Square Institute of Neurology, for this contribution. To read about Dr Wykes’ current ERUK-funded project with Professor Kirill Volynski, click here.