Personalized ASO Gene Therapy Dramatically Reduces Seizures and Restores Walking in Children with SCN2A-Related Epilepsy
核心洞察
Two children with SCN2A-related developmental epileptic encephalopathy (搜索) received allele-selective antisense oligonucleotides (搜索) tailored to their individual mutations in n-of-1 trials published in Nature Medicine.
The 14-year-old patient experienced a 90% reduction in seizure frequency and walked independently for the first time at age 15, while the 9-year-old saw a 26% drop.
Both patients showed developmental gains in language, motor skills, and adaptive behaviors, with no serious adverse events reported over the two-year treatment period.
An international research team led by the University of California San Diego and Rady Children's Institute for Genomic Medicine (搜索) has demonstrated that gene therapy tailored to an individual patient's specific genetic mutation can dramatically reduce seizure frequency and produce meaningful developmental gains in children with SCN2A-related developmental epileptic encephalopathy (搜索) (DEE). The findings, published on July 21, 2026 in Nature Medicine, emerge from two separate n-of-1 clinical trials conducted over a two-year period.
SCN2A (搜索)-related DEE is a rare, severe form of childhood epilepsy and one of the most common causes of monogenic autism. The condition arises from single mutations to the sodium voltage-gated channel alpha subunit (SCN2A) gene, which governs the flow of sodium ions into neurons. These mutations — most of which are de novo, arising spontaneously rather than being inherited — promote abnormal brain excitability, leading to uncontrolled seizures, developmental delays, autism, movement problems, and gastrointestinal issues. Traditional anti-seizure medications are often ineffective and do not address the underlying genetic cause.
"We've seen changes across the board, showing that targeting the root genetic cause can produce measurable improvement," said principal investigator Olivia Kim-McManus, MD, associate professor of neurosciences at UC San Diego School of Medicine and director of the Rady Precision Therapeutics Neuro-Interventional Program at Rady Children's Hospital San Diego.
How the Allele-Selective ASO Approach Works
Each person carries two copies of every gene, and SCN2A (搜索) mutations affect only one of the gene's two copies. The researchers designed short, synthetic pieces of DNA called allele-selective antisense oligonucleotides (搜索) (ASOs) that recognize harmless regions of DNA adjacent to each child's disease-causing mutation. "The therapy is deliberately designed to target the individual's genetic diagnosis," Kim-McManus explained. "The ASO modifies genetic expression and what proteins are expressed."
The ASOs were injected under anesthesia directly into the spinal fluid, silencing the mutant version of the gene while allowing the healthy copy to function normally. The therapy was administered every two to three months, with each child serving as their own control.
Dramatic Seizure Reductions and Developmental Milestones
The two patients, aged nine and 14 at the start of their clinical studies, showed markedly different but clinically meaningful responses. The 14-year-old patient experienced a 90% reduction in seizure frequency, eventually achieving stretches of seizure-free days. The nine-year-old patient, who had seizures nearly every day, experienced a 26% drop in seizure frequency.
Beyond seizure control, both patients were able to cut back or stop some of their anti-seizure medications. Both also showed improvements in language and motor skills, sensory processing, and adaptive behaviors, with a reduction in autism-related behaviors. In a striking developmental milestone, the older patient walked independently for the first time at age 15. His chronic gastrointestinal issues also improved, requiring less medication.
Safety Profile and Dosing Adjustments
No serious side effects or ASO-related adverse events were reported throughout the two-year study period. Routine lab tests, electrocardiograms (ECGs), and electroencephalograms (EEGs) remained stable.
Because the therapy affects gene expression without permanently altering the underlying genetic code, it must be administered at regular intervals. During the trial, the older patient's ability to walk independently began to wane before the next scheduled dose, prompting the researchers to adjust the dosing frequency with FDA approval. "Since then, he's been walking independently," said Kim-McManus. "When we really think about precision therapy in a personalized way, you can't get more personalized than that."
A Model for Monogenic Disease
While these therapies remain investigational, Kim-McManus emphasized that 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," she said. "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."
The study was funded in part by the California Institute for Regenerative Medicine (grant #CLIN2-15085). Co-authors include researchers from UC San Diego, Rady Children's Institute for Genomic Medicine (搜索), the n-Lorem Foundation, Ionis Pharmaceuticals (搜索), Rush University Medical Center, Boston Children's Hospital and Harvard University, and the University of Melbourne.