Individualized gene therapy shows early promise for SCN2A-related epileptic encephalopathy

Two first-in-human clinical trials suggest that individualized antisense oligonucleotide (ASO) therapy may offer a disease-modifying treatment option for children with SCN2A-related developmental epileptic encephalopathy (DEE), a rare genetic disorder characterized by early-onset seizures and neurodevelopmental impairment. Investigators reported reductions in seizure frequency, improvements in neurodevelopment, and no ASO-related serious adverse events in 2 children treated with personalized therapies designed specifically for their disease-causing genetic variants.^1,2

Speaking about the findings, Olivia Kim-McManus, MD, associate professor of neurosciences at the University of California San Diego and pediatric neurologist and epileptologist at Rady Children's Health, emphasized that SCN2A-related disorders affect children early in life and extend well beyond seizures.

“The developmental epileptic encephalopathies, or the DEE, are a group of disorders that are characterized by developmental delay or regression in infants and children, as well as seizures that are often early onset around the time of infancy or early childhood,” Kim-McManus said.

She explained that SCN2A encodes a sodium channel critical for neuronal communication. Variants affecting the gene disrupt normal brain signaling, leading to developmental delay, regression, and refractory epilepsy. Current antiseizure medications may help control seizures but generally are not designed to target the underlying genetic defect.

How does personalized antisense therapy differ from traditional seizure medications?

“Anti-seizure medications…are already FDA approved, and they're not usually targeted for a specific gene or a specific variant,” Kim-McManus said. “This is different in terms of a genetic therapy or gene therapy in that it's targeted towards actual change in the DNA specific to an individual or individual disease presentation.” She added that the approach represents “precision or personalized medicine because the therapeutic is designed against an individual variant.”

The study evaluated 2 boys, aged 9 and 14 years, each with distinct SCN2A variants causing severe DEE. Personalized allele-selective ASOs were developed to suppress the disease-causing gene copy while preserving expression of the normal allele. One patient experienced an estimated 26% reduction in seizures, while the second had an estimated 90% reduction. Both patients also had fewer concomitant antiseizure medications, prolonged seizure-free intervals, and no seizure-related emergency department visits or hospitalizations after treatment began.

What improvements did investigators observe beyond seizure reduction?

Beyond seizure control, investigators observed improvements across multiple developmental domains. Communication, motor skills, adaptive behavior, and gastrointestinal symptoms improved in one or both patients, with no ASO-related serious adverse events reported during follow-up.

Kim-McManus noted that both participants entered the trials well beyond infancy, when many clinicians would expect developmental gains to be limited.

“These children that we went into N-of-1 trials for were older children. One was around 10 at the beginning of the study, and the other was closer to almost 15,” she said. “One significant impact for one of the patients, the older one, is that he was non-ambulatory his whole life and began walking after starting this therapy, and you know has had sustained independent gait at 15 years of age.”

She said those findings suggest that opportunities for neurologic improvement may extend beyond the earliest developmental windows.

“Earlier you would think theoretically is better in terms of optimizing an infant or child's developmental potentials, but also teaching us that there is potential for continued improvement or intervention in later stages,” Kim-McManus said.

Can personalized dosing improve outcomes for children with SCN2A-related disorders?

Investigators also individualized treatment after observing that one patient's symptoms returned before the next scheduled dose. Following an FDA-approved protocol amendment that shortened the dosing interval, the patient regained sustained seizure control and maintained independent walking.

“Can you personalize somebody's therapeutic regimen that is optimized further for one individual? You can,” Kim-McManus said, while noting that such adjustments occurred within an investigational regulatory framework.

Could this approach expand to more children with rare neurologic diseases?

Although the study included only 2 patients, investigators believe the approach could extend beyond individualized treatment. Genetic analysis identified additional patients with SCN2A-related disorders who may be eligible for similar therapies, supporting the possibility of expanding personalized ASOs to broader groups of patients with rare neurologic diseases.

“We don't want to end at the single patients,” Kim-McManus said. “The fact that we are seeing safety and efficacy in these two, that we want to see potential impact for more children, including with SCN2A-related disorders as well as other monogenic neurologic conditions where this type of genetic intervention is feasible.”

Disclosure: Kim-McManus reports no competing interests.

References

1. Kim-McManus O, Mignon L, Douville J, et al. Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy. Nat Med. Published online July 2026. doi:10.1038/s41591-026-04527-y

2. UC San Diego. Personalized Gene Therapy Helps Teen with Rare Form of Severe Epilepsy Walk Independently. Newswise. July 21, 2026. Accessed July 22, 2026. https://www.newswise.com/articles/personalized-gene-therapy-helps-teen-with-rare-form-of-severe-epilepsy-walk-independently/?sc=mwhr&xy=10069075