New Gene Therapy Approach May Control Epileptic Seizures Caused by Focal Cortical Dysplasia

Focal Cortical Dysplasia (FCD) is a type of disorder caused by abnormal cortical development, often accompanied by drug-resistant epilepsy and cognitive and behavioral disorders. According to the classification criteria proposed by Najm et al. in 2022 for the International League Against Epilepsy (ILAE), FCD can be further divided into isolated types (FCD I and II) and FCD III associated with primary lesions. Among them, FCD II is mainly caused by somatic mutations, leading to cortical layering disorders and malformed neurons, which are integrated into pro-epileptic brain circuits. Recently, Barbanoj et al. from the Queens Square Institute of Neurology at University College London experimentally discovered a gene therapy method that can effectively reduce epileptic activity in FCD II, bringing new hope for the prevention of FCD-related epilepsy.

Research Background and Author Information

This study was published in the July 2024 issue of “Neurosci. Bull.”, titled “Raising new hope for controlling seizures in focal cortical dysplasia with gene therapy”. The research was jointly completed by Yuanzhi Yang, Yang Zheng, Zhong Chen, and Cenglin Xu, all affiliated with the Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences. This article was submitted on December 29, 2023, accepted on February 7, 2024, and published online on May 11, 2024.

Research Process

The primary goal of the study was to simulate FCD II and reduce seizure frequency through gene therapy. The research team first established a RhebCA mouse model by in utero electroporation-mediated expression of Rheb (Ras homolog enriched in brain) to simulate the pathological conditions of FCD II. Typical ectopic, malformed, and enlarged neurons appeared in the prefrontal cortex of electroporated mice. This evidence suggests that the model is similar to FCD II patients.

To further characterize the epileptic phenotype of FCD II mice, researchers conducted continuous cortical EEG recordings and observed various types of epileptic activity, including significant leading spikes, high-frequency “chirps”, and typical intermittent seizure manifestations. In addition, the study found that spontaneous generalized seizures mainly occurred during the light period of the 24-hour circadian cycle, consistent with the circadian rhythm of epileptic activity in clinical patients. Given the common cognitive and behavioral disorders in FCD II patients, researchers conducted a series of behavioral tests and found impaired learning ability in T-maze and social cognitive deficits in olfactory discrimination tests in FCD II mice.

Next, the researchers used AAV virus-encoded engineered potassium channels (EKC) for gene therapy. Continuous baseline EEG recordings were performed for 15 days before and after EKC transfection, and seizure frequencies were compared before and after gene therapy. The results showed that gene therapy reduced seizure frequency by an average of 87%, with a relative reduction in epileptic peaks noted after treatment. Additionally, they tested the effect of gene therapy on behavioral phenotypes and found that while gene therapy significantly suppressed seizures, it had no significant effect on behavioral deficits in FCD II mice.

Research Results

The research results show that the team successfully established the RhebCA model, with mice exhibiting clinical symptoms of FCD II. They further demonstrated the effectiveness of EKC gene therapy on spontaneous seizures in FCD II mice, although it had no significant effect on behavioral deficits. Specific data showed that gene therapy reduced seizure frequency by an average of 87%, and the peak frequency of seizures relatively decreased, highlighting the important role of potassium channels in alleviating seizures.

Research Conclusions and Value

The research team successfully simulated FCD II clinical symptoms by establishing the RhebCA mouse model and effectively reduced intractable spontaneous seizures using EKC gene therapy. This breakthrough laboratory study provides a highly promising treatment approach for FCD II-related intractable epilepsy. Researchers suggest that future studies could further explore whether EKC gene therapy can effectively treat other types of FCD or other types of intractable drug-resistant epilepsy. Moreover, the combination of gene editing technologies such as CRISPR-Cas9 may further enhance the translational significance of EKC gene therapy.

The different effects of gene therapy on seizures and behavioral disorders reflect different mechanisms. Seizures are mainly associated with neuronal hyperexcitability, while behavioral disorders may be related to more complex neural circuit dysfunctions, which is also worth further study. To better achieve therapeutic effects and reduce side effects, gene therapy techniques need to be more personalized and time-effective.

Research Highlights

1. Successfully established a RhebCA mouse model simulating FCD II.
2. EKC gene therapy significantly reduced seizure frequency without significant impact on behavioral deficits.
3. Provided a novel and potentially promising treatment approach that may be applicable to other types of FCD and intractable epilepsy.

Suggestions for Further Research

Future research should continue to explore the potential application of EKC gene therapy in other FCD types and intractable epilepsy. At the same time, it is crucial to explore the mechanisms of gene therapy’s effects on behavioral disorders and strengthen the application of gene editing technologies in gene therapy.

Summary

This article details a new gene therapy method for controlling epileptic seizures caused by focal cortical dysplasia. By establishing an FCD II mouse model and using EKC gene therapy, seizure frequency was significantly reduced, bringing new hope for the treatment of FCD-related epilepsy. This study lays the foundation for future in-depth exploration of gene therapy applications in other types of epilepsy and provides valuable data support and theoretical basis for related fields.