Personalized gene therapy helps teen with rare form of severe epilepsy walk independently

SCN2A-related developmental epileptic encephalopathy (DEE) is a rare, severe form of childhood epilepsy and one of the most common causes of monogenic autism. The condition is caused by single mutations 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, resulting in uncontrolled seizures along with developmental delays, autism, movement problems and gastrointestinal issues. Most of these mutations are de novo (not inherited from a parent) and arise spontaneously.

Traditional antiseizure medications are often ineffective and do not address the underlying genetic cause of SCN2A-related DEE.

Now, an international team of researchers led by the University of California San Diego and Rady Children's Institute for Genomic Medicine has treated two children with the condition using gene therapy tailored to each child's specific SCN2A mutation.

In two separate n-of-1 clinical trials over a two-year period, the children, ages 9 and 14 at the beginning of their clinical studies, showed a dramatic drop in seizure frequency in addition to developmental gains, with minimal side effects.

The studies, published in Nature Medicine, pave the way for scaling personalized therapies from "one-off" cases to larger groups of patients with similar genetic backgrounds.

Silencing the faulty gene copy

Each person has two copies of every gene, and SCN2A mutations affect only one of the gene's two copies. The researchers created short, synthetic pieces of DNA called allele-selective antisense oligonucleotides (ASOs) that recognize harmless regions of DNA next to each child's disease-causing mutation.

"The therapy is deliberately designed to target the individual's genetic diagnosis," said principal investigator Olivia Kim-McManus, MD, associate professor of neurosciences at UC San Diego School of Medicine, director of the Rady Precision Therapeutics Neuro-Interventional Program at Rady Children's Hospital San Diego, and clinical investigator and physician-scientist at Rady Children's Institute for Genomic Medicine. "The ASO modifies gene expression and the proteins expressed."

Injecting the ASOs under anesthesia directly into spinal fluid silenced the mutant version of the gene while allowing the other copy of the gene to function normally.

The therapy was repeated every two to three months, with each child serving as their own control. The researchers tracked seizure counts, medication use and a range of developmental and behavioral measures before and after treatment. After two years, they found:

• Decreases in seizure frequency:

  • The 9-year-old patient, who had seizures nearly every day, experienced a 26% drop in seizure frequency.

  • The 14-year-old patient experienced a 90% reduction in seizure frequency, eventually reaching stretches of seizure-free days.

• Reduced medication load:

  • Both patients were able to cut back or stop some of their antiseizure drugs.

• Developmental gains:

  • Both patients showed improvements in language and motor skills, sensory processing and adaptive behaviors, with a reduction in autism-related behaviors.

  • The older patient walked independently for the first time at age 15.

• Other health benefits:

  • The older patient's chronic gastrointestinal issues improved, requiring less medication.

• Safety:

  • No serious side effects or ASO-related adverse events were reported.

  • Routine lab tests, electrocardiograms (ECGs) and electroencephalograms (EEGs) remained stable.

"We've seen changes across the board, showing that targeting the root genetic cause can produce measurable improvement," Kim-McManus said.

Dosing adjusted to sustain gains

Because the therapy affects gene expression but doesn't permanently change the underlying genetic code, it must be administered at regular intervals. During the trial, the older patient's ability to walk on his own began to wane before the next dose was administered, so the researchers adjusted the dosing frequency with FDA approval.

"Since then, he's been walking independently," Kim-McManus said. "When we really think about precision therapy in a personalized way, you can't get more personalized than that."

Kim-McManus said that while these therapies are still investigational, they provide a model for rapidly translating personalized genetics into treatments, potentially accelerating development for many other neurological and non-neurological diseases caused by single-gene mutations.

"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," Kim-McManus said. "But now that we're on the other side showing safety and efficacy, the idea is spreading beyond academia to the pharmaceutical and biotech industries and having a big impact."

Publication details

Individualized Antisense Oligonucleotides for SCN2A Related Developmental Epileptic Encephalopathy, Nature Medicine (2026). DOI: 10.1038/s41591-026-04527-y

Journal information:Nature Medicine

Source: https://medicalxpress.com/news/2026-07-personalized-gene-therapy-teen-rare.html