Novel gene therapy shows promise for targeting epilepsy-linked mutation

Researchers at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS Medicine) are working on a therapy that could treat patients with epilepsy, a neurological disorder defined by recurrent seizures due to abnormal brain activity .

Led by Research Assistant Professor Huang Hua from the Department of Physiology and Electrophysiology at NUS Medicine, they tested a new gene therapy approach for a rare genetic form of epilepsy linked to a mutation in the KCNA2 gene in the human brain, which is associated with recurrent seizures.

A specialized treatment called Gapmer antisense oligonucleotide (ASO) is designed to specifically target and break down defective ribonucleic acids (RNA) while keeping normal gene function intact. Use of this RNA therapy resulted in a notable decrease in a problematic potassium channel protein encoded in the KCNA2 gene, which helped restore normal potassium flow and reduce excessive neuronal activity linked to epilepsy .

Assistant Professor Huang said: “Epilepsy is associated with hyperexcitable neurons, and potassium helps dampen excitability levels. The potassium channel encoded by KCNA2 is like a gate that controls the flow of potassium ions to the surface of cells, when the gene is mutated the gate no longer functions and potassium cannot be released to control neuronal activity, which leads to epilepsy.

“Our therapy targets the faulty RNA in the gene and ‘fixes the door,’ so potassium can flow and regulate neuronal activity levels.”

Published in Molecular therapy – Nucleic acidsThe research study was conducted on in vitro cell samples. The research began in 2021, when the team was approached by the family of an infant suffering from multiple generalized seizures resistant to several medications and conventional treatments.

Although the research is in its early stages and will need further testing in laboratory models before moving into clinical trials, the remarkable research results provide hope that the therapy can be administered to patients suffering from severe epilepsy caused by channelopathies (genetic disorders). caused by abnormalities in the ion channels of cells, in the next 10 to 20 years.

The new Gapmer technology the research team is working on could also be adapted to target other mutations in the same or other ion channel genes, opening up the possibility of creating personalized treatments for different KCNA2-related problems, offering potentially promising results for affected patients. rare forms of epilepsy that do not respond to standard medications.

Professor Soong Tuck Wah from the Department of Physiology and Electrophysiology at NUS Medicine, co-author of the study, said: “Our research not only aims to address the unique challenges posed by this specific mutation, but also arises from efforts of our team. desire to improve the quality of life of patients.

“Since the therapy has shown promise in targeting a specific genetic mutation causing epilepsy, we hope to eventually provide new treatment options for patients suffering from this and other similar genetic mutations.”