Scientists reverse severe epilepsy in laboratory mouse models in promising step towards cure
Base editing approach reverses pathogenic SCN8A mutation in mice, with reduced seizure burden, improved survival and restored neuronal function pointing towards future gene therapies for severe inherited epilepsies
A highly precise form of gene editing has corrected the underlying genetic defect responsible for a severe inherited epilepsy in a preclinical study, with researchers reporting marked reductions in seizure activity and improved survival in treated animals.
Scientists at the University of Virginia School of Medicine, Charlottesville, Virginia, USA, have used base editing to repair a pathogenic mutation in the SCN8A gene which underlies SCN8A developmental and epileptic encephalopathy. This rare but severe condition presents in early infancy and is characterised by recurrent seizures, developmental delay, movement disorders and a substantial risk of sudden unexpected death in epilepsy. The findings have suggested that targeted correction of disease-causing mutations may offer a route towards disease-modifying or potentially curative therapies for genetic epilepsies.
SCN8A-related epilepsy is estimated to affect approximately one in 56,000 births and accounts for around one per cent of all epilepsy cases, although underdiagnosis remains likely. The disorder arises from gain-of-function mutations in the SCN8A gene, which encodes a voltage-gated sodium channel critical for neuronal signalling. These mutations permit excessive sodium influx into neurons which drives pathological hyperexcitability and lowers the threshold for seizure generation.
“Historically, treatments addressed only the downstream effects of genetic mutations. [However] today we can correct the mutations themselves and target the root cause of disease,” said Dr. Manoj Patel, who led the study at the University of Virginia’s Department of Anesthesiology and the University of Virginia Brain Institute.
“Base editing opens the door to the treatment of numerous genetic diseases, not only those associated with epilepsy, and has the potential to significantly improve patients’ quality of life,” he said.
To address the underlying molecular defect, Patel and colleagues deployed base editing, a next-generation genome engineering approach that permits direct conversion of individual nucleotides without the need to introduce double-strand DNA breaks. This precision reduces the risk of unintended genomic alterations that can occur with earlier gene-editing techniques and makes the approach particularly attractive for neurological applications, where off-target effects could have profound consequences.
In the study, the researchers applied base editing to correct the SCN8A mutation in a mouse model that recapitulates key features of the human disease. Treated animals showed either complete elimination or substantial reduction in seizure frequency. Survival improved significantly, and the mice demonstrated enhanced motor function alongside reduced anxiety-like behaviours, which serve as a surrogate measure of neurological and cognitive improvement in preclinical models.
Detailed electrophysiological and molecular analyses have confirmed that the intervention achieved its intended biological effect. Sodium influx into neurons decreased following treatment, and neuronal hyperexcitability – which underpins seizure activity – diminished accordingly. These findings have provided mechanistic evidence that precise genetic correction can restore more normal neuronal function in this disease context.
“This shows that the devastating impact of the mutation is not permanent and can be reversed,” said Dr. Caeley Reever, the study’s lead researcher.
“We were able to effectively ‘cure’ mice carrying this specific gene mutation – a mutation that is known to cause epilepsy in some children,” she said.
The clinical implications remain prospective, and translation to human therapy will require extensive further work to establish safety, delivery efficiency and long-term durability of effect. Nevertheless, the results have reinforced the broader therapeutic potential of base editing as a platform technology for monogenic neurological disorders.
“Our goal is to assess this gene therapy in children with this specific SCN8A variant,” Patel said.
“Recent advances in gene therapy offer significant promise for patients with genetic diseases. Instead of addressing only the consequences, these approaches enable direct targeting of the underlying cause – the pathogenic genetic mutation itself – with real potential for a cure,” he added.
The research aligns with wider institutional efforts at the University of Virginia to accelerate translational biotechnology. The Paul and Diane Manning Institute of Biotechnology, in collaboration with the University of Virginia Brain Institute, has focused on development of innovative therapeutic strategies for complex neurological diseases, including epilepsy and Alzheimer’s disease.
For further reading please visit: 10.1172/JCI196402