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Congratulations are in order to Dr Jose Prius Mengual who has been awarded an Emerging Leader Fellowship Award from Epilepsy Research UK and the Nucleic Acid Therapy Accelerator (NATA). With this award, Dr Mengual will develop a new genetic therapy to rebalance protein levels in the neurons affected by epilepsy to prevent seizures.

© Kavli INsD

Around 1 in every 100 people in the UK have epilepsy. 70% of these are successfully treated by current antiepileptic treatments, but the remaining 30% are resistant, leaving only very aggressive interventions available to them. These individuals have a significant risk of sudden death in epilepsy (SUDEP). Furthermore, misdiagnosis of epilepsy is fairly commonplace, so the number of people living untreated with epilepsy may be even higher. Over the past decade, there have been few advances made in clinical interventions against epilepsy, so further research into the molecular and network mechanisms underlying epileptic seizures is vital for improving treatments.

Sleep and epilepsy have a well-known, but little understood reciprocal relationship. Sleep disturbances are two to three times more prevalent in people with epilepsy, and the treatment of sleep disorders is known to improve seizure control. For some time now, clinicians have scheduled video electroencephalographs to record brainwaves of children with suspected epilepsy in the morning after a night of sleep deprivation and certain antiepileptic medications have long been known to induce drowsiness, yet we have only recently begun to better understand the intersection between epilepsy and sleep. We do know that during normal wakefulness, we accumulate defective proteins in the endoplasmic reticulum (ER) of neurons, causing ER stress. During seizures in epilepsy, this ER stress is also triggered inside neurons and it may be implicated in the pathogenesis of epilepsy, leaving a gap in our knowledge around the molecular mechanisms for protein balance in the context of epilepsy.

Dr Jose Prius Mengual from the Vyazovskiy group based at the Kavli Institute for NanoScience Discovery has been awarded a 2-year Epilepsy Research UK & NATA Emerging Leader Fellowship Award to characterise the relationship between epilepsy, sleep and ER stress. Dr Mengual will use a novel conditional knockout animal model to reveal the molecular mechanisms linking synaptic function, neural excitability and unfolded protein response, and investigate whether modulation of ER stress pathways linked to sleep can prevent seizures.

Dr Mengual says: “The goal of this research is finding a genetic therapy that goes beyond treating seizures and restores healthy brain function in individuals with epilepsy. During seizures, there is an accumulation of defective proteins that disturbs the normal physiology of neurons. Also, during wakefulness, we naturally accumulate these proteins, and in both cases, brain cells activate the same molecular pathway to restore healthy protein levels. Therefore, manipulating the genes involved could help restore protein balance, allowing neurons to focus their energy on achieving a healthy synaptic communication.

“Developing new technology to modify genes in the brain is challenging, but treating a novel mouse model of epilepsy with these therapies is a promising first step toward human application. My research seeks to transform how we treat epilepsy by finding a long-term physiological therapy that goes beyond treating the manifestations of epilepsy and fully recovers normal brain function.

“The approach of helping neurons with their molecular problems to restore their functionality has not been deeply studied yet in epilepsy. Furthermore, the development of genetic therapies that can reach and interact with the brain is a much-desired technique that is not yet fully developed. One of the strengths of this project is how easily adaptable it is because it can be used to manipulate the expression of almost any gene in the brain. Once fully developed, it will open the door to other researchers to try out their own ideas and potentially originate more new genetic treatments. Evolving from the use of artificial drugs to genetic therapies makes me really excited about the potential to change the lives of people impacted by epilepsy.”

Dr Mengual will develop the gene modification technology with NATA in Professor Colin Akerman’s laboratory in the Department of Pharmacology before conducting the in vivo work in Professor Vladyslav Vyazovskiy’s laboratory in the Kavli Institute for NanoScience Discovery.

Prius Mengual in the lab© Epilepsy Research UK

Epilepsy Research UK CEO Maxine Smeaton says: "This fellowship, in partnership with the MRC Nucleic Acid Therapy Accelerator, will enable Dr Mengual to develop a track record in innovative nucleic acid therapeutics and to do so with the support of NATA's world-leading scientists and state-of-the-art facilities. This project has the potential to accelerate the development and delivery of life changing and much needed therapies for people with epilepsy."

Executive Director of NATA Nick Lench says: "NATA is committed to providing training and support to the next generation of science leaders. Our focus on inter-disciplinary and translational research will enable Dr Mengual to develop the skills and experience to succeed in this exciting co-funded fellowship with Epilepsy Research UK, which aims to develop nucleic acid therapies that could significantly improve the management and treatment of epilepsy."

More information about Dr Mengual’s project “New therapies against epilepsy combining sleep and cellular stress genes” is available to read on the Epilepsy Research UK website, which includes video spotlight.