SCN2A-associated developmental epileptic encephalopathy (DEE) is a rare and severe form of childhood epilepsy and one of the most common causes of monogenic autism. This condition is caused by a single mutation in the sodium voltage-gated channel alpha subunit (SCN2A) gene, which controls the flow of sodium ions into neurons. These mutations promote abnormal brain excitability, leading to uncontrollable seizures with developmental delays, autism, movement disorders, and gastrointestinal problems. Most of these mutations are de novo (rather than inherited from a parent) and occur naturally.
Conventional anti-seizure drugs are often ineffective and do not address the underlying genetic causes of SCN2A-related DEE. Now, an international research team led by the University of California, San Diego and the Rady Institute for Pediatric Genomic Medicine has treated two children with the disease using gene therapy tailored to each child’s specific SCN2A mutation. In two n-of-1 clinical trials over a two-year period, children who were 9 and 14 years old at the start of the clinical study experienced a dramatic reduction in seizure frequency, with minimal side effects. This study was published on July 21, 2026. natural medicinepaves the way for extending personalized treatment from “one-off” cases to larger groups of patients with similar genetic backgrounds.
Each person has two copies of every gene, and the SCN2A mutation affects only one of the two copies of the gene. The researchers created short pieces of synthetic DNA called allele-selective antisense oligonucleotides (ASOs) that recognize a harmless region of DNA next to each child’s disease-causing mutation.
“This therapy is intentionally designed to target an individual’s genetic diagnosis,” said lead investigator Olivia Kim McManus, MD, associate professor of neuroscience at the University of California, San Diego School of Medicine, director of the Rady Precision Therapeutics Neurointerventions Program at Rady Children’s Hospital in San Diego, and a clinician and physician-scientist at Rady Children’s Institute for Genomic Medicine. “ASOs change gene expression and what proteins are expressed.”
Injecting ASO directly into the spinal fluid under anesthesia silenced the mutated version of the gene, allowing other copies of the gene to function normally.
This treatment was repeated every 2 to 3 months, with each child serving as his or her own control. The researchers tracked seizure frequency, drug use, and various developmental and behavioral measures before and after treatment. Two years later, they discovered:
- Reduced seizure frequency:
- This 9-year-old patient, who had been having seizures almost every day, saw a 26% reduction in seizure frequency.
- The 14-year-old patient experienced a 90% reduction in seizure frequency and eventually experienced seizure-free days.
- Reduced drug load:
- Both patients were able to reduce or discontinue some of their antiepileptic medications.
- Developmental benefits:
- Both patients showed improvements in language and motor skills, sensory processing and adaptive behaviors, and decreased autism-related behaviors.
- This elderly patient first walked independently at age 15.
- Other health benefits:
- Chronic gastrointestinal problems in older patients improved and required less medication.
- Safety:
- No serious side effects or ASO-related adverse events were reported.
- Routine laboratory tests, electrocardiogram (ECG) and electroencephalogram (EEG) remained stable.
“We’re seeing changes across the board, showing that targeting the underlying genetic cause can lead to measurable improvements,” said Kim McManus.
Although this treatment affects gene expression, it does not permanently change the underlying genetic information and must be administered regularly. During the trial, the elderly patients’ ability to walk unaided began to decline before the next dose, so researchers adjusted the dosing frequency with FDA approval.
He has been walking independently ever since. If you’re serious about precision treatment in a personalized way, it doesn’t get any more personalized than that. ”
Dr. Olivia Kim McManus, Associate Professor of Neuroscience, University of California, San Diego School of Medicine
She says that while these treatments are still in the research phase, they provide a model for rapidly translating personalized genetics into treatments and have the potential to accelerate the development of many other neurological and non-neurological diseases caused by single gene mutations.
“This is like a sci-fi or Star Trek idea, and that’s the look I used to see when I first started doing this,” Kim McManus said. “But now that it has been proven safe and effective, the idea has spread beyond academia and into the pharmaceutical and biotech industries, making a huge impact.”
sauce:
University of California, San Diego
Reference magazines:
Kim McManus, O. others. (2026). Personalized antisense oligonucleotides for SCN2A-associated developmental epileptic encephalopathy. natural medicine. DOI: 10.1038/s41591-026-04527-y. https://www.nature.com/articles/s41591-026-04527-y
