Epilepsy Research Institute Partner Symposium: Radically advancing research into epilepsy

Abstract

On 28 April 2025, the Epilepsy Research Institute Symposium at BNA2025 brought together four early career researchers to present on their findings in different areas of fundamental epilepsy research. Here, we provide a snapshot of the Symposium and highlights from the researchers’ talks.

Launching in October 2023, the Epilepsy Research Institute (ERI) aims to transform epilepsy research. Guided by the robust James Lind Alliance priority-setting process (Norton et al., 2025), the Institute focuses on six main themes – Advanced Therapeutics and Disease Modification; Reproduction and Hormones; Neurodevelopment; Mortality, Morbidity and Risk; Capacity Building and Enabling Technology. Each theme is led by a core research group and supported by an international task force.

Supporting talented early career researchers (ECRs) to develop their skills and expertise is central to the Institute’s mission. At the BNA2025 Epilepsy Research Institute Partner Symposium ‘Radically advancing research into epilepsy’, four emerging researchers presented their work, which ranged from basic science to translational models and therapies with potential clinical applications. The development of novel strategies to treat epilepsies was a key theme throughout the symposium.

Targeting epileptic seizures and cognitive comorbidities with a novel gene therapy

Dr Amy Richardson, an ERI Emerging Leader fellow at University College London, presented her work on developing a gene therapy to treat focal epilepsies. Her approach enhances GABAergic inhibition at the epileptic focus by restoring disrupted chloride gradients that are critical for seizure control. She demonstrated successful delivery of the therapy to the brain, effectively increasing the target protein in chronic epilepsy. This increase in protein was associated with decreased duration of seizure-like events in brain slices and a decreased severity of acute seizures in a rodent model of status epilepticus.

While promising, further research is needed to determine efficacy against spontaneous seizures and ensure safety before clinical application. Research into gene therapies to treat epilepsy has gained traction in recent years, as they offer the potential to treat the underlying disease mechanisms of epilepsy while protecting against side effects that so often accompany small-molecule treatments. As a result, ‘Advanced Therapeutics’ was listed as a top research priority by the ERI. Discussions with the audience raised important questions about scaling gene therapies from animal models to humans and the challenges of clinical delivery of gene therapies, key topics within the ERI ‘Advanced Therapeutics’ theme.

Reprogramming of reactive glia into fast-spiking interneurons in a mouse model of mesial temporal lobe epilepsy

Dr Nicolas Marichal, ERI Emerging Leader Fellow at the Centre for Developmental Neurobiology, King’s College London, presented his work on reprogramming glial cells into interneurons in a mouse model of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), a prevalent form of human epilepsy. MTLE-HS is characterised by a loss of GABAergic interneurons, especially parvalbumin-expressing (PV+) interneurons, leading to reduced inhibition. Glial-to-neuron conversion is a new avenue for the restoration of diseased brain circuits (Leaman et al., 2022). Dr Marichal showed previously published work demonstrating that reactive glia in the MTLE-HS hippocampus can be converted using transcription factors Ascl1 and Dlx2 into interneurons, reducing spontaneous recurrent seizures, although these cells lacked PV+ features (Lentini et al., 2021). However, using a mutant variant of Ascl1, Ascl1SA6, Dr Marichal showed that glia in the early postnatal cortex were converted into PV-expressing neurons, capable of high-frequency firing (>120 Hz), hallmarks of PV+ interneurons (Marichal et al., 2024). He showed preliminary results employing the Ascl1 mutant in the MTLE-HS mouse model and detailed future experiments designed to assess network connectivity in Ascl1SA6-derived interneurons and their impact on seizure control.

While glia-to-neuron conversion holds therapeutic promise, audience questions highlighted the challenges for clinical translation. Questions included whether the astrocyte population within the hippocampus may become depleted if they are converted to interneurons and whether the Moloney murine leukaemia virus (MMLV)-based viral vector, used in proof-of-principle studies, would be translatable to human treatment. Dr Marichal explained that glial proliferation after injury likely prevents astrocyte loss and associated negative effects and that although MMLV is specific for the transduction of proliferative cells such as reactive glia, emerging adeno-associated virus (AAV) vectors with astrocyte-targeting promoters may allow more translatable viral strategies for clinical interventions.

New therapies against epilepsy combining sleep and cellular stress genes

Dr Jose Prius Mengual, ERI and NATA Emerging Leader Fellow at the Kavli Institute for Nanoscience Discovery, University of Oxford, described his work to identify new time windows and molecular targets for pharmacological intervention with newly synthesised antisense oligonucleotides (ASOs) that target endoplasmic reticulum (ER) stress genes in a mouse model of genetic-generalised epilepsies.

Dr Mengual presented preliminary data on his fellowship project which aimed to use brain activity patterns during sleep to monitor the efficacy of ASO treatments for epilepsy. There is a strong relationship between sleep, ER stress and epilepsy. Using a conditional Tbc1d24 knockout mouse model, a gene associated with several types of epilepsy in humans (Finelli et al., 2019), Dr Mengual showed that changes to electroencephalogram (EEG) spectral power precede seizure onset, particularly in non-rapid eye movement (NREM) and rapid eye movement (REM) phases of sleep. Once mice develop seizures, NREM sleep patterns are disturbed with a delayed latency to NREM sleep compared to control mice. These findings suggest that sleep-related brain activity could serve as a sensitive marker to guide ASO treatment timing and support long-term recovery of brain function. Dr Mengual concluded by suggesting that the technique could help detect or broaden windows for pharmacological intervention with ASOs to support their preventive or curative effects in the brain and the long-term recovery of normal brain function.

Dr Mengual emphasised that epilepsy treatment should address not only seizures but also comorbidities like sleep disruption, to achieve true disease-modifying effects with real impact for people with epilepsy. Important questions from the audience were raised following Dr Mengual’s talk including the cell-specificity of his ASO treatment and whether the therapy could be made to target cells that are more susceptible to ER stress. He explained that, in contrast to viral therapies which include promoters to drive cell-specific targeting, ASOs treat all cells within the vicinity of the treated brain area. The main advantages of ASO therapies over viral-based therapies may be the lack of toxicity due to further ER stress induction and the absence of permanent changes in gene expression due to the lack of direct gene editing. A significant point was also raised here that is applicable to all epilepsy research and that is the importance of studying both male and female subjects to assess sex differences and ensure that any treatment options discovered in the laboratory are efficacious across the whole epilepsy population.

Advancing models of glioblastoma-related epilepsy through network-level approaches

Dr Kate Hills, a postdoctoral researcher at University College London, presented her PhD work on developing a model of glioblastoma-related epilepsy to understand the mechanisms behind seizure development and to develop new therapies. Using longitudinal electrocorticography combined with magnetic resonance imaging, she demonstrated a dynamic interplay between tumour growth and network hyperexcitability. The model also revealed region-specific alterations in astrocytic glutamate clearance, implicating the peritumoural microenvironment as a key modulator of excitability and seizure susceptibility. Her findings highlight the importance of incorporating models of epilepsy as a comorbidity into mainstream epilepsy research and suggest new avenues for exploring the functional impact of tumour growth on neural circuits.

Audience discussions centred on the potential of this platform to inform both mechanistic studies and therapeutic targeting of the tumour-adjacent microenvironment and highlighted the need for clinically relevant animal models.

Reflections

These are exciting times for research in epilepsy. The symposium reflected how ECRs are developing novel strategies for seizure control across diverse forms of epilepsy, and the active engagement of the audience through questions and discussions confirmed a strong interest in the topics presented.

Developing new technologies for treatment remains a vital area of investigation for the epilepsy field. However, translational work is complex, expensive, challenging and very time-consuming. Supporting ECRs with substantial and sustained funding is therefore essential to build sufficient capacity and promote their full commitment to this challenge. This will be crucial to advance preclinical basic research towards clinical trials that can make a real impact on people affected by epilepsy. Emerging Leader Fellowship Awards from the ERI are an outstanding example of initiatives dedicated to empowering early career scientists in the epilepsy field. However, due to budget constraints, the extent of the fellowship (2 or 3 years) is usually not enough to complete ambitious, translational research goals. Therefore, increased funding is vital to ensure that we retain talented ECRs in the epilepsy field and enable them to advance their novel ideas and technologies towards impactful treatments, a top research priority for epilepsy.

Taken together, the Epilepsy Research Institute Symposium at the BNA2025 meeting provided a valuable forum to contextualise emerging strategies to treat epilepsy that are being tested in preclinical models and to reflect on their potential to inform therapeutic development.