Personalised gene therapy shows promise for rare childhood epilepsy

A new personalised genetic therapy has shown early success in treating two children with a rare genetic epilepsy syndrome.

SCN2A-related developmental and epileptic encephalopathy (DEE) is a type of childhood epilepsy caused by mutations in the SCN2A gene. Affected children experience severe treatment-resistant seizures and developmental delays. Clinicians have developed a new experimental therapy using synthetic strands of DNA, known as antisense oligonucleotides (ASOs), which target the underlying genetic mutation. Treatment of two affected children over two years showed a strong reduction in seizure frequency alongside improvements in communication and motor skills.

'The therapy is deliberately designed to target the individual's genetic diagnosis. The ASO modifies genetic expression and what proteins are expressed,' said Dr Olivia Kim‑McManus, associate professor of neurosciences at the University of California San Diego School of Medicine, and lead investigator of the study published in Nature Medicine.

SCN2A encodes a key component of an ion channel that controls the flow of sodium into neurons. Changes in sodium levels affect the excitability of neuronal networks in the brain, leading to uncontrolled seizures in patients with SCN2A-related DEE. Mutations usually only affect one copy of the gene and most arise spontaneously rather than being inherited from a parent. Traditional seizure medications do not treat the underlying genetic cause and are ineffective.

Researchers at the University of California San Diego and Rady Children's Institute for Genomic Medicine in San Diego, California, have developed ASOs that only target the disease-causing allele. These short, synthetic strands of DNA were tailored to each patient to bind specifically to the mutated copy of the gene using nearby genetic markers. This selectively reduced expression of the faulty gene while preserving the healthy copy.

ASOs were injected into the fluid surrounding the spinal cord every two to three months so that the therapy would reach the brain. Both patients, aged nine and 14, showed noticeable improvements and no serious side effects were reported in response to the treatment to date. However, the reduction in seizure frequency varied substantially, from 26 percent in the youngest child and up to 90 percent in the teenager.

'It's like a sci-fi, Star Trek idea, and that's the look that I used to get when I was just starting this. But now that we're on the other side showing safety and efficacy, the idea is spreading beyond academia to the pharma and biotech industry and having a big impact,' said Dr Kim‑McManus.

The study involved only two patients and was designed as an early proof-of-concept investigation. Because each ASO was tailored to an individual's genetic variant, the treatment cannot be applied directly to all children with SCN2A-related DEE. The study also did not include a control group, instead comparing each patient's outcomes with their own pre-treatment seizure activity and developmental progress. The researchers said that continued long-term follow-up will be needed to confirm the safety, durability and disease-modifying potential of this personalised approach.