Emerging Gene Therapy Approaches for Epilepsy: A Path to Precision Treatment
By Shivani Narasimhan
As of 2024, precise global data on the proportion of idiopathic epilepsy cases are limited. However, a recent population-based cohort study in Denmark reported that idiopathic epilepsy accounted for approximately 62% of total epilepsy cases in that population. According to the International League Against Epilepsy, idiopathic epilepsy (epilepsy with no identifiable underlying cause) accounts for approximately 52.3% of all active epilepsy cases worldwide. The following table gives a short summary of the statistics of Epilepsy worldwide based on the Seizure Types.
Epilepsy Type
Statistics
Tonic-clonic seizures
Most Common
Temporal Lobe Seizures
Most Common
Frontal Lobe Seizures
Second most Common
Parietal Lobe Seizures
5% of all forms of epilepsy
Occipital Lobe Seizures
5% of all epileptic seizures
Absence Seizures
2% - 8% of people with epilepsy
With recent advances in genetic sequencing, researchers have found some single-gene forms of epilepsy where a specific inherited or new mutation causes the condition. Most of these cases involve changes in ion channels (like SCN1A for sodium channels). Other types of epilepsy, including some acquired cases, are now believed to involve multiple genes working together with environmental factors. However, finding the genetic cause in these cases is challenging due to differences among individuals and complex genetic patterns. Identifying mutations is also tough because the same mutation can lead to different phenotypes, while different mutations can give rise to similar phenotypes.
Latest Gene therapy Research in Childhood Epilepsy (UCL)
Current research on Gene Therapy for epilepsy primarily aims to alleviate symptoms through the use of viral vectors, such as adeno-associated viruses and other similar platforms. Advances in gene-editing technologies, particularly CRISPR/Cas9, have opened new avenues for epilepsy treatment. However, clinical application remains challenging due to persistent issues related to vector delivery, model reliability, expression control, and ethical considerations.
A team of researchers at UCL Queen Square Institute of Neurology exploited gene therapy techniques to cure a devastating form of childhood epilepsy - Focal Cortical Dysplasia (FCD, Common cause of Drug Resistant Epilepsy).
Figure 1: A study published in Brain aimed to identify an alternative to surgery for treating children with focal cortical dysplasia.
FCD occurs due to abnormalities in the development of certain brain regions and is one of the most frequent causes of drug-resistant epilepsy in children. It often affects the frontal lobe, involved in planning and decision-making. The researchers at UCL evaluated the potential of gene therapy based on the overexpression of potassium channels to regulate neuronal excitability. Potassium channels play a crucial role in regulating hyperexcitability, minimizing the intensity of seizures. Consequently, the researchers developed a potassium channel gene and inserted them into an epileptic mice using viral vectors. Consequently, the researchers observed that the gene therapy could reduce seizures by 87% as compared with the control groups, in mice. Following this successful observation, it was highlighted that this methodology could be suitable for clinical translation and deployed in children suffering from uncontrolled seizures.
GAPMER Technology - Novel Gene Therapy Method (NUS Medicine)
A team of researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) developed a Gene Therapy approach, in an attempt to treat a rare genetic form of epilepsy associated with KCNA2 gene mutation triggering recurrent seizures. KCNA2 gene encodes potassium channels that help regulate potassium ion flow, controlling neuronal excitability. The research began in the year 2021, when the team had witnessed an infant suffer from multiple generalized seizures, resistant to drugs and conventional treatments. The study was conducted on in vitro samples using GAPMER Technology - designed to break down the faulty RNA molecules, preserving the normal function of the KCNA2 gene and restoring the potassium ion flow thereby controlling epileptic activities in the brain. This research is said to be in the Preclinical Stages, however, could potentially offer remarkable results for candidates with channelopathies in this decade.
While the majority of gene and cell therapies have not yet transitioned into widespread clinical use, significant strides have been made in this field. Preclinical studies in animal models are actively underway, and an increasing number of clinical trials are being initiated to rigorously evaluate the safety and efficacy of these approaches. Given the complex and heterogeneous nature of epilepsy's onset and progression, the development of gene and cell therapy techniques represents a transformative opportunity to advance treatment strategies and improve patient outcomes.
References
https://www.sciencedirect.com/science/article/pii/S0753332221008581
https://jnnp.bmj.com/content/early/2024/11/12/jnnp-2024-334547
https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.868531/full
