Novel gene therapy shows promise in targeting a mutation linked to epilepsy microbiologystudy

Researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) are working on a therapy that holds potential in treating patients with epilepsy, a neurological disorder defined by recurring seizures due to abnormal brain activity.

Led by Research Assistant Professor Huang Hua from the Department of Physiology and Electrophysiology Core Facility at NUS Medicine, they have trialed a novel 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 recurring seizures.

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

Asst Prof Huang said, “Epilepsy is associated with hyper-excitable neurons, and potassium helps dampen the excitability levels. The potassium channel encoded by KCNA2 is like a door that controls the potassium ion flow on the surface of the cells—when the gene is mutated, the door fails to work and potassium cannot be released to control neuron activity, which results in epilepsy.

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

Published in Molecular Therapy—Nucleic Acids, the research study was conducted on in vitro cell samples. The research work began in 2021, when the team was approached by the family of an infant who suffered from multiple generalized seizures that were resistant to multiple medications and conventional treatments.

While the research work is in early stages and will need to undergo further testing in laboratory models before moving to clinical trials, the remarkable results from the research offer hope that the therapy can be delivered to patients suffering from severe epilepsy caused by channelopathies—genetic disorders caused by abnormalities in the ion channels of cells—within the next 10 to 20 years.

The new Gapmer technology being worked on by the research team could also be adapted to target other mutations in the same gene or other ion channel genes—opening the possibility of creating personalized treatments for different KCNA2-related issues, potentially offering hopeful outcomes for patients with rare forms of epilepsy that are unresponsive to standard medications.

Professor Soong Tuck Wah from the Department of Physiology and Electrophysiology Core Facility at NUS Medicine, a co-author of the study, said, “Our research seeks not only to address the unique challenges posed by this specific mutation, but also stems from our team’s desire to improve the quality of life for patients.

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