Research has shown early diagnosis and treatment of epilepsy disorders can improve outcomes. The question of when to administer treatment so it gets ahead of the disease, however, has remained stubbornly elusive.
A new Northwestern University study suggests intervention could start during pregnancy - as early as 15 weeks gestation - well before symptoms appear, highlighting the potential benefit of treating certain epilepsy disorders as early as possible.
"We want to better understand things happening in the brain in utero that result in deficits to hopefully establish models and therapeutics that prevent the damage so the brain can develop under its normal timeline," said corresponding author Richard Smith, assistant professor of pharmacology and pediatrics at Northwestern University Feinberg School of Medicine.
The study reveals for the first time how a novel RNA‑based treatment affects brain cell signaling when applied at early stages of development in a rare, severe and treatment‑resistant form of epilepsy caused by changes in a gene called KCNT1. If given very early - possibly even in utero, or for preterm infants - the treatment may help protect the developing brain from hyper-excitation, a means to reduce long‑term neurological harm, the study found.
"The early brain is an amazingly plastic structure," Smith said. "If we miss a therapeutic window, it becomes much harder to reverse the damage later as we manage symptoms in patients."
The findings were published April 29 in Nature Communications.
What is KCNT1-related epilepsy?
KCNT1-related epilepsy affects approximately 3,000 people worldwide. Children with KCNT1-associated epilepsy of infancy with migrating focal seizures (EIMFS) can have dozens or even hundreds of seizures a day, often don't respond to standard treatments and face a high risk of early death.
Using brain cells grown in the lab from children with a severe KCNT1 mutation, the scientists showed these cells produce excessive electrical activity, which helps explain why these children have seizures.
The scientists then tested an experimental RNA-based therapy, called an antisense oligonucleotide (ASO) aimed at reducing KCNT1 activity on lab-grown neurons. The therapy co-developed by the Smith lab recently showed promising results in patients. In the new study, it successfully reduced the abnormal electrical currents in patient-derived excitatory neurons (functional brain cells manufactured in the lab from a patient's own cells).
The scientists also tested the therapy in developing human brain cells equivalent to the middle of pregnancy (15 to 21 weeks gestation) and found it reduced excessive firing at this early stage, too. These findings establish a key clinical basis for targeting the perinatal period, Smith said.
Why timing matters
Early treatment of a disease depends on early diagnosis, which remains a major challenge, Smith said.
Although most genetic changes are present at conception, they might not be detectable or cause symptoms until later. For instance, some conditions can be observed early in gestation (e.g. spina bifida), some after birth (e.g. infantile epileptic encephalopathy), while others don't appear until childhood (e.g. muscular dystrophy) or even adulthood (e.g. Huntington's disease). This wide range can make it difficult to know when it's possible to diagnose a genetic disease, let alone begin to treat it. Most routine prenatal tests can only detect large genetic changes while often missing single‑gene disorders like KCNT1‑related epilepsy.
"A big thrust of my lab is thinking how far back we can go to understand a disease to build prophylactic therapies," Smith said. "First, we have to know whether there's even a biological target to engage because early brain development can be a black box."
When a condition is not identified before birth, rapid genetic testing after delivery can now provide a diagnosis within days, allowing treatment to begin soon after birth, Smith said.
What's next
The study found adjusting the brain's natural "cool-down" signal after a neuron fires (a process known as afterhyperpolarization) can meaningfully influence how brain cells behave. Future research aimed at strengthening this cooling‑off process, particularly in living brains where neurons fire in complex patterns, could help scientists better understand and eventually treat a wide range of neurological disorders driven by overly excitable brain cells, Smith said.
The study is titled, "RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death."
Other Northwestern study authors include Sean Golinski, Karla Soriano, Alex Briegel, Madeline Burke, Sheng Tang and Gemma Carvill.
Funding for the study was provided by the National Institute of Neurological Disorders and Stroke grants R00NS112604 and R01NS140046) and the National Institute of Allergy and Infectious Diseases (DP2NS148744), both part of the National Institutes of Health, and the Bachrach Family Foundation.
