Gene therapy significantly reduces seizures in epilepsy mouse model

A new gene therapy has been successfully tested in mice that could provide an alternative to surgery in children with drug resistant epilepsy.

Focal cortical dysplasia is one of the most common causes of drug resistant epilepsy in children. It is caused by abnormal organisation of neuronal networks, and to date surgery has been the most effective treatment. However, seizures may still occur post-surgery and it can be associated with permanent neurological damage. Using gene therapy to overexpress a potassium channel has now been shown to effectively reduce seizures in a mouse model of focal cortical dysplasia.

'It is very exciting to see that this new gene therapy could potentially be used as an effective alternative to surgery in patients with focal cortical dysplasia,' said Professor Gabriele Lignani from the Queen Square Institute of Neurology, University College London (UCL), one of the senior authors of the study.

Abnormal neuronal development and organisation in focal cortical dysplasia occurs frequently in the frontal lobes, an area of the brain that is important in decision making. Affected individuals also often experience behavioural and cognitive impairments, such as learning disabilities. Gene therapy has been shown to be effective for seizures originating in the temporal lobes, but this is the first time it has been used to reduce seizure activity in the frontal lobe.

Overexpression of the KCNA1 gene that encodes the KV1.1 potassium channel subunit has previously been shown to reduce seizure activity in several mouse models. In the study published in Brain, researchers engineered a potassium channel transgene so that expression would be higher in the neurons that are hyperexcitable in the disease.

The potassium channel was delivered to the frontal lobe of mice by a viral vector, that is unable to replicate or cause diseases. Gene therapy reduced seizure frequency by 64 percent and also significantly reduced spike frequency, but no changes were observed in mice treated only with a control virus. The treatment had no negative impact on mouse behaviour, but also did not improve behavioural phenotypes observed in the mice. This suggests that gene therapy is successful in treating seizures, but not the accompanying cognitive impairments.

'Following the successful study in mice, we believe the treatment is suitable for clinical translation, and, taking into account the size of the unmet need, it could be deployed to thousands of children who are currently severely affected by uncontrolled seizures,' said Dr Vincent Magloire from UCL and lead author of the study.

This gene therapy has to date only been tested in mice, however the researchers involved aim to initiate the first human clinical trial in mid-2025.