A personalized gene therapy has dramatically reduced seizures and enabled a teenager with a rare form of severe epilepsy to walk independently for the first time, researchers at UC San Diego and Rady Children's Institute for Genomic Medicine reported on July 21 in Nature Medicine.

The Condition

SCN2A-related developmental epileptic encephalopathy (DEE) is a rare, severe childhood epilepsy caused by a single mutation in the SCN2A gene, which controls sodium flow into neurons. The mutation causes abnormal brain excitability, leading to uncontrolled seizures, developmental delays, autism, and movement problems. Standard anti-seizure drugs rarely help because they don't address the root genetic cause.

The Therapy

The researchers designed custom short DNA strands called allele-selective antisense oligonucleotides (ASOs) — essentially molecular patches that recognize the specific mutation in each child's SCN2A gene. Injected into spinal fluid every two to three months, the ASOs silenced the mutant gene copy while leaving the healthy copy untouched.

"The therapy is deliberately designed to target the individual's genetic diagnosis," said Dr. Olivia Kim-McManus, associate professor at UC San Diego School of Medicine and lead investigator. "When we really think about precision therapy in a personalized way, you can't get more personalized than that."

The Results

After two years of treatment: - A 14-year-old patient had a 90% reduction in seizure frequency, eventually reaching stretches of seizure-free days. He walked independently for the first time at age 15 and his chronic gastrointestinal issues improved. - A 9-year-old patient with near-daily seizures experienced a 26% drop in seizure frequency, plus improvements in language, motor skills, and sensory processing. - Both patients reduced or stopped some anti-seizure drugs. - No serious side effects were reported.

What's Next

Because ASOs don't permanently change the genetic code, treatment must continue at regular intervals. The team adjusted dosing frequency with FDA approval when the older patient's walking ability began to wane before the next dose — and he regained it.

"It's like a sci-fi, Star Trek idea," 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."

The approach provides a scalable model for rapidly translating personalized genetics into treatments for many other neurological and non-neurological single-gene diseases.

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