Two children with one of the most severe forms of childhood epilepsy have seen their seizures fall dramatically after receiving gene therapies designed for their individual mutations – a result researchers say points the way toward personalised medicine on a much wider scale.
The boys, aged nine and 14 when their treatment began, both have SCN2A-related developmental epileptic encephalopathy, a rare disorder caused by a single faulty gene that governs how sodium flows into brain cells. The mutation drives runaway electrical activity, producing relentless seizures alongside developmental delays, movement problems and, often, autism. Standard anti-seizure drugs frequently fail because they do nothing about the underlying genetic fault.
Silencing the faulty copy
An international team led by the University of California San Diego and the Rady Children's Institute for Genomic Medicine took a different route. Each child carries two copies of the SCN2A gene, only one of which is mutated. The researchers built short synthetic strands of DNA – allele-selective antisense oligonucleotides – that latch onto markers beside the faulty copy and switch it off, while leaving the healthy copy working. Delivered into the spinal fluid under anaesthesia every two to three months, the therapy was tailored to each patient's precise diagnosis.
Over two years, with each child acting as their own control, the gains were striking. The nine-year-old, who had seizures almost daily, saw them drop by about a quarter; the 14-year-old's seizures fell by 90 percent, with stretches of seizure-free days. Both were able to reduce their medication, and both made broad developmental progress in language, motor skills and behaviour, with fewer autism-related traits. The older boy walked independently for the first time.
Reported on 21 July in Nature Medicine, the two n-of-1 trials were led by neurologist Olivia Kim-McManus. Beyond the two families involved, the researchers say the approach offers a template for rapidly turning a genetic diagnosis into a treatment – potentially for many other conditions caused by single-gene mutations.