Epilepsy-Related Mutation Targeted by Novel Gene Therapy

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Researchers at the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) are working on a treatment that has the potential to treat patients with epilepsy, a neurological disorder characterized by frequent seizures due to of abnormal brain activity.

Led by Research Assistant Professor Huang Hua from the Department of Physiology and Electrophysiology Core Facility at NUS Medicine, they tested a new gene therapy approach for a rare type of epilepsy associated with epilepsy mutation. KCNA2 genes in the human brain, associated with frequent seizures. A special treatment called Gapmer antisense oligonucleotide (ASO) is designed to specifically target and destroy faulty ribonucleic acids (RNA) while maintaining normal gene function. Using this RNA therapy led to a noticeable reduction in the amount of potassium-deficient protein that was added to the KCNA2 gene, which helped restore normal potassium flow and reduce the neuron overactivity associated with epilepsy.

Asst Prof Huang said, “Epilepsy is associated with overactive nerves, and potassium helps to lower excitatory levels. The potassium channel activated by KCNA2 it’s like a gate that controls the flow of potassium ions across cells—when the gene is altered, the gate fails to function and potassium cannot be released to regulate neuron activity, resulting in epilepsy. Our treatment targets the faulty RNA in the gene and ‘fixes the door’, so that potassium can flow in and regulate neuron activity levels. Asst Prof Huang is also from the Healthy Longevity Translational Research Program at NUS Medicine.

Published in Molecular Therapeutics Nucleic Acidsa top journal in the field of nucleic-acid-based therapeutics, a research study was conducted by in vitro cell samples. The research work began in 2021, when the team was approached by the family of a baby who suffered from multiple seizures and was resistant to many medications and conventional treatments. Although the research work is in the early stages and will need to be further tested in laboratory models before moving to clinical trials, the impressive results of the research give hope that the treatment can be given to patients with the disease of severe epilepsy caused by channelopathies-genetic disorders. caused by abnormalities in the cell’s ion channels – over the next 10 to 20 years.

Professor Soong Tuck Wah of the Department of Physiology and Electrophysiology Core Facility at NUS Medicine, co-author of the study, said, “Our research not only seeks to address the unique challenges posed by this particular mutation, but also from our group.’s desire to improve patients’ lives. Since the treatment has shown promise in targeting the specific genetic mutation that causes epilepsy, we hope to eventually open up new treatment options. for patients with this condition, and other similar genetic changes.” Prof Soong is also from NUS Medicine’s Healthy Longevity Translational Research Programme.

Reference: Huang H, Ma DR, Chan DWS, et al. Targeting multiple negative heterozygous variants of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy. Molecular Therapy – Nucleic Acids. 2024;35(4):102316. doi: 10.1016/j.omtn.2024.102316

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