A two-year treatment targeting proteins produced by disease-causing mutations dramatically reduced seizures and led to developmental gains, including helping one teenager walk independently.
For children with SCN2A-related developmental epileptic encephalopathy (DEE), seizures can begin alongside serious delays in movement, communication, and other abilities. The rare childhood epilepsy is also one of the most common causes of autism linked to a mutation in a single gene.
The disorder develops when one mutation affects the sodium voltage-gated channel alpha subunit (SCN2A) gene, which regulates the movement of sodium ions into neurons. These mutations can make brain cells abnormally excitable, contributing to uncontrolled seizures, developmental delays, autism, movement difficulties, and gastrointestinal problems. Most arise de novo (not inherited from a parent), meaning they occur spontaneously.
Standard anti-seizure medications often provide limited relief and do not correct the genetic mechanism driving SCN2A-related DEE. An international group led by the University of California San Diego and Rady Children’s Institute for Genomic Medicine therefore developed treatments matched to the specific SCN2A mutation carried by each of two children.
The children were nine and 14 when their separate n-of-1 clinical trials began, meaning each treatment was designed and evaluated for one person. Over two years, both experienced substantial declines in seizure frequency, developmental improvements, and few side effects. Published in Nature Medicine, the studies provide a possible framework for extending highly personalized treatments beyond isolated cases to larger groups with similar genetic profiles.
A custom therapy silences one mutation
People carry two copies of each gene, and SCN2A mutations typically affect only one copy. The researchers designed short synthetic strands of DNA known as allele-selective antisense oligonucleotides (ASOs). Each ASO recognized a harmless stretch of genetic material located beside the disease-causing mutation in that child.
“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 genetic expression and what proteins are expressed.”
Doctors delivered the ASOs directly into the spinal fluid while each child was under anesthesia. The treatment suppressed activity from the mutated copy of SCN2A while leaving the unaffected copy able to work normally.
Seizures decline as development improves
Each child received another dose every two to three months and served as their own control. The researchers compared seizure frequency, medication use, development, and behavior before and after treatment. After two years, the results included:
- Decreases in seizure frequency:
- The nine-year-old patient, who previously experienced seizures almost every day, had a 26% decrease in seizure frequency.
- The 14-year-old patient had a 90% reduction in seizure frequency and eventually experienced periods of seizure-free days.
- Reduced medication load:
- Both children reduced or discontinued some of their anti-seizure medications.
- Developmental gains:
- Both children improved in language, motor abilities, sensory processing, and adaptive behavior, while autism related behaviors decreased.
- At age 15, the older patient walked independently for the first time.
- Other health benefits:
- The older patient’s long-standing gastrointestinal problems improved, reducing the need for medication.
- Safety:
- Researchers reported no serious side effects or adverse events related to the ASOs.
- Routine laboratory testing, 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,” said Kim-McManus.
Benefits depend on repeated dosing
The treatment changes how the gene is expressed rather than permanently rewriting the genetic code, so regular doses are necessary. During the trial, the older patient began losing some of his ability to walk independently as the next scheduled treatment approached. With FDA approval, the researchers shortened the interval between doses.
“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 personalized genetic medicine
Kim-McManus cautioned that the treatments remain investigational. Even so, the studies demonstrate how an individual genetic diagnosis can be rapidly translated into a personalized therapy. The same approach could potentially speed treatment development for other neurological and non-neurological conditions caused by mutations in a single gene.
“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,” said Kim-McManus. “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.”
Reference: “Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy” by Olivia Kim-McManus, Laurence Mignon, Julie Douville, He Pu, Catherine Parisien, Sarah Glass, C. Frank Bennett, Janelle Celso, Kendall Robbins, Hoameng Ung, Heather Olson, Stephen F. Kingsmore, Steven Petrou, Stanley T. Crooke, Joseph G. Gleeson and Elizabeth Berry-Kravis, 21 July 2026, Nature Medicine.
DOI: 10.1038/s41591-026-04527-y
The work at Rush was supported by the RUMC N-of-1 Fund. Research at UCSD was supported by the California Institute for Regenerative Medicine (grant CLIN2-15085 to O.K.-M.).
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