Project: EpiGlymph - Redefining epilepsy treatment - the role of waster clearing in the brain
Challenge Space
Health - Resistance
Principal Investigator(s) and team names
Dr Janosch Heller, Toby Segasby (PhD student)
Collaborating Institutions
Medical University Innsbruck, Austria; Lund University, Sweden; Royal College of Surgeons in Ireland, Ireland; FutureNeuro Research Ireland Centre for Translational Brain Science, Ireland
Funding support
Research Ireland Starting Laureate Award (IRCLA/2022/3828)
Project start date
1 September, 2022
End date
Current
Problem
Epilepsy affects more than 70 million people worldwide and over six million people across Europe.
Despite the availability of numerous anti-epileptic drugs (AEDs), approximately 30% of patients remain resistant to treatment.
Pharmacoresistant temporal lobe epilepsy (TLE) is particularly challenging, leaving many patients with ongoing seizures, reduced quality of life, increased risk of injury, severe comorbidities, and a substantially elevated risk of sudden
unexpected death in epilepsy (SUDEP).
Surgical resection remains the only effective treatment for many refractory patients, yet it is unsuitable for the vast majority of individuals with epilepsy.
Background
Most existing epilepsy therapies target neurons through modulation of ion channels or neurotransmitter receptors.
However, growing evidence suggests that astrocytes, the housekeepers of the brain, play a central role in seizure generation and the development of epilepsy.
In healthy brains, astrocytes regulate neurotransmitter uptake, maintain potassium homeostasis, and facilitate brain fluid/waste clearance through the glymphatic system.
In epilepsy, these functions become disrupted, resulting in elevated extracellular potassium and glutamate concentrations that promote neuronal hyperexcitability. Key proteins involved in these processes, including the potassium channel Kir4.1, aquaporin-4 (AQP4), and components of their scaffolding apparatus, are frequently mislocalised or reduced in epileptic tissue.
Solution
This project is developing and evaluating novel astrocyte-targeted therapeutic strategies aimed at restoring brain homeostasis in epilepsy.
By enhancing the function and localisation of Kir4.1, AQP4, and their scaffolding components, we seek to improve spatial potassium buffering and glymphatic waste clearance, two critical mechanisms disrupted in pharmacoresistant epilepsy.
The project combines advanced molecular, imaging, and translational approaches to determine whether restoring astrocyte function can reduce seizure susceptibility, prevent disease progression, and provide a disease-modifying alternative to current neuron-centred treatments.
Ultimately, this research could establish astrocytes as a new therapeutic target class for epilepsy and open new avenues for treating patients who currently have limited options.