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Research Portfolio

GRANT TITLE:

EPILEPSY RESEARCH UK & NATA FELLOWSHIP AWARD

grant amount:

£245,962 over 24 months, awarded in 2023

SCIENTIFIC TITLE:

Antiepileptic chronotherapies targeting ER stress related genes

lead investigator:

Dr José Prius Mengual

Co-Investigators:

- Supervisor: Professor Vladyslav Vyazovskiy (University of Oxford)- Supervisor: Professor Colin Akerman (University of Oxford)

institution:

University of Oxford

Background

Approximately 30% of people with epilepsy do not respond to current treatments. Further understanding of the molecular and network mechanisms that underlie seizures is therefore vital. Sleep disturbances are two to three times more prevalent in people with epilepsy, and the treatment of sleep disorders can improve seizure control. The link between sleep and epilepsy remains unclear, but a potential mechanism is the accumulation of defective proteins due to failures in cellular transportation. This accumulation, called ER stress, increases with the amount of time spent awake. Activation of ER stress pathways relates to abnormal neuronal excitability and even cell death, suggesting a new and previously unexplored mechanism.

"During my previous MRC early career position, I collaborated in investigating the molecular and electrical signatures of epilepsy in the brain. This experience has made me acutely aware of the pressing need for novel approaches in treatments against epilepsy. My innate curiosity and drive to improve things have motivated me to develop a project focused on genetic therapies that will ultimately result in better clinical interventions and aim to significantly improve the lives of people affected by epilepsy. I am eagerly looking forward to seeing the positive impact my efforts will have on people’s lives.

The Study

This project aims to investigate whether modulation of ER stress pathways linked to sleep, using novel nucleic acid therapeutics (NATs) in the brain, can prevent seizures.

This research will use a new experimental model of a genetic cause of epilepsy, based on the selective loss-of-function of the gene TBC1D24. This gene is responsible for a range of recessive genetic epilepsies, including encephalopathy, and may be linked to sudden unexpected death in epilepsy (SUDEP). The gradual reduction of protein expression levels over several weeks gives us the opportunity to explore the early onset of seizures. To establish seizure frequency, brain activity will be measured with recordings from different regions in an area of the brain called the cortex. Changes in sleep and wake over time will be analysed with molecular techniques to measure gene and protein expression.

Significance

This collaboration with NATA will allow the creation of nucleic acid therapeutics (NATs) targeting genes of the ER stress pathways, expanding our knowledge of the relationship between epilepsy and sleep and the mechanisms underlying epilepsy, with the potential for new and much-needed treatment options.