Their names are confidential, but their story and contribution to the field of rare disease are not. Patient one was born as an apparently healthy baby girl and discharged quickly after birth. However, on her fourth day of life, the seizures — unrelenting at several dozen a day — began, and she was rehospitalized. It wasn’t long before she was diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS), a severe neurodevelopmental disorder. At 28 months, she was generally healthy but had shown little neurological development. She was hypotonic and had between several and 20 seizures every day (1).

She was not alone in her devastating diagnosis. Within five hours of being born, another little girl began seizing, her tiny body pausing its breath as her legs bicycled. This is patient two (1).

At two years old, she experienced severe global developmental delay. She could intentionally grasp objects but was unable to hold onto them. She maintained eye contact but had difficulty tracking. She couldn’t roll over completely yet, but she seemed to understand simple words and commands. She had a social smile, and her parents said she appeared alert and aware of her surroundings. However, ten to fifteen times every day, often during her afternoon naps, her body would stiffen, and her head would turn to one side as she underwent a focal tonic seizure. In one hour, she could have up to eight brief seizures, each less than two minutes long (1).

EIMFS (Epilepsy of Infancy with Migrating Focal Seizures), a form of KCNT1-related epileptic encephalopathy, is associated with seizures, intense neurological impairment, and premature death. Infants with this condition begin seizing within the first several days of life and may have dozens of seizures a day. Currently, there are no truly effective treatments for this condition. Quinidine may be partially helpful in some patients but shows inconsistent efficacy and is often not tolerated. Nearly half of patients with KCNT1-related EIMFS die before the age of three (1).

“The EIMFS form is among the most serious neonatal epilepsies we know of,” explains Dr. Timothy Yu, who led the study that looked at how the two little girls might respond to an investigational ASO.

The condition is caused by a dysfunction of the sodium-activated potassium channel known as Slack. Slack, encoded by the KCNT1 gene, is expressed in neurons throughout the central nervous system and modulates neuronal firing patterns and excitability. In EIMFS, a genetic variant of KCNT1 leads to an overactive Slack channel, increasing total neuronal potassium currents by up to 40% and causing cortical hyperexcitability that results in seizures (1).

Knowing the disease is driven by gain-of-function KCNT1 mutations that produce overactive channels, Dr. Yu says lowering the channel expression is a rational strategy, and an RNase H gapmer that reduces KCNT1 mRNA is a direct way to do it.

“What motivated the study was the chance to test that idea (whether reducing KCNT1 could actually change the course of the disease) where the need was greatest — in patients with EIMFS,” he says, adding that their research is part of a broader effort to address the long tail of rare disease — the thousands of monogenic conditions that are so rare they are beyond the reach of conventional drug development programs.

The study, recently published in Nature Medicine, examined an investigational KCNT1-targeting antisense oligonucleotide (ASO), known as valeriasen, which significantly reduced seizure frequency and intensity in the two little girls. However, it was also associated with the development of hydrocephalus, a condition characterized by excess fluid buildup in the brain (1).

Valeriasen: faster and more complete than predicted 

In September 2020, patient one, now three years old, joined the trial and began receiving escalating intrathecal valeriasen doses of 10 mg, 20 mg, 30 mg, and 40 mg via lumbar puncture at weeks 0, 2, 4, and 6. At 10 weeks, maintenance dosing of 40 mg began, administered every 8 weeks. At week 26, the maintenance dose was increased to 60 mg every 8 weeks. During the study, she showed improved seizure frequency and severity compared with her pretreatment baseline. Her EEG background during wakefulness showed diffuse, generalized slowing with frequent multifocal spikes, and a suppression-burst pattern during sleep. No major changes in EEG background patterns were found during the trial (1).

Nine months later, patient two, also three years old, started the study. She received the same escalating doses as patient one, and began to show an improvement in her seizure frequency at her 20 mg dose and an even more significant improvement after 30 mg. During this time, her family noticed positive changes at home, including better head control, swallowing, and self-soothing by chewing on her fingers. Right before her fourth dose, EEGs showed a 50% seizure reduction from baseline. After her fourth dose, her seizures dropped to 0-3 per day for nearly 50 days. Like patient one, her EEG background did not change significantly over time (1).

“The effect on seizure suppression was faster and more complete than our preclinical data could have predicted,” says Dr. Yu. However, the disease’s extreme early onset means that years of uncontrolled seizures could have already produced injury by the time treatment began at age 3.

Safety and unexpected side effects           

Cerebrospinal fluid (CSF) and blood safety lab results were unremarkable during the study’s first ten months, and quantitative sensory testing showed no significant changes in mechanical detection thresholds or pain thresholds. Four months into the trial, patient one developed dystonia, involuntary muscle contractions that cause abnormal, often twisting movements or postures. The dystonia was a serious adverse event but was of uncertain correlation with the ASO, given that KCNT1-related epilepsy sometimes causes the condition. After evaluations with specialists, her dystonia was treated with a course of clonazepam, baclofen, and gabapentin, and improved (1). Dosing continued for eight more months and seemed to be well tolerated.

However, approximately 11 months into the trial, patient one’s family reported the development of intermittent nausea. Neurologic exam showed increased muscle tone. Brain and spine imaging revealed an unexpected finding of severe communicating hydrocephalus. Patients with early-onset KCNT1-related epilepsy commonly develop cortical atrophy, which can lead to ex vacuo ventricular enlargement; however, hydrocephalus was not an expected symptom of the disease, nor was it observed in the animal studies. After discussions with her care team, the family decided to withdraw from the study and place her in palliative care. Three months after her final ASO dose, she died under hospice care (1).

Two months before these events for patient one, the other little girl entered the study (patient 2). Her first three doses were well tolerated, but a few days after her 40 mg dose, she developed dystonia. An LP was within normal limits, and an initial brain MRI was unremarkable, but follow-up brain imaging showed progressive increases in ventricular size. There was no evidence of obstruction. Due to the hydrocephalus found in patient one, patient two was transferred to the pediatric intensive care unit and had a ventriculoperitoneal shunt placed. Her ventricular dilatation gradually normalized. After one month, she was discharged home in a stable condition (1).

Ventricular enlargement: a cautionary lesson

Investigational dosing was paused as the researchers re-evaluated, worked with the FDA on delivery methods, and developed a safer protocol. During the hiatus, patient two’s seizures returned to pretreatment baseline levels. Two years later, her ASO administration resumed; however, intracerebroventricular (ICV) dosing was used instead of intrathecal, which was well-tolerated and led to a 75% reduction in seizures (1).

“Encountering ventricular enlargement linked to high-dose intrathecal ASO administration was an important cautionary lesson,” says Dr. Yu. “Our experience also provided some human pilot data (albeit with only a single patient) that intracerebroventricular dosing can be a viable delivery route.”

Possible reasons for IT delivery of an ASO triggering ventricular enlargement or hydrocephalus are unclear, but the authors posit that it could involve changes in CSF overproduction, decreased CSF resorption, or alterations in ventricular compliance. They note this particular adverse event has not been reported in other IT ASO trials for conditions like Angelman syndrome, Dravet syndrome, SOD1-related ALS or FUS-related ALS. “One possibility is that this adverse event could be a potential side effect triggered by high doses of some but not all high-dose ASOs,” the authors state (1).

Dr. Yu says that there is reason to think this may be seen in other CNS-deployed ASOs rather than something unique to valeriasen, as tominersen (an RNase H gapmer with a closely related backbone chemistry to valeriasen) has been linked to ventricular enlargement at high doses in Huntington’s disease (1). “This realization changed our approach to dose escalation and monitoring in our CNS ASO programs.” Why the ventricular enlargement occurred remains an important unanswered question, he adds. The hypothesis that a possible class effect of some high-dose IT gapmers could affect CSF production, resorption, or compliance remains unproven and is an active research priority.

“We have a clinical observation, but no direct mechanistic data; developing in vitro and in vivo models to study it is an active area of investigation. On first principles, inflammation is a reasonable hypothesis, but the assays we ran (in human peripheral blood or Bjab-cell assays) did not reflect it,” he explains. However, he says that’s not a reason to dismiss inflammation as a hypothesis, but a reason to keep watching for it, since more sensitive or as-yet-unpublished methods might reveal something new.

Consequential findings and unanswered questions

The most consequential finding is that seizures in humans can change quickly and dramatically when KCNT1 expression and channel function are reduced, indicating that knockdown of an overactive channel can be a tractable therapeutic strategy, explains Dr. Yu. He continues that the monitoring framework they used for safety — serial opening pressures and periodic MRI with ventricular volumetry — is simple for others to consider adopting, especially for individuals with neurologic impairments in whom signs or symptoms of intracranial pressure elevations may be difficult to detect. Regarding delivery, their experience suggests ICV administration deserves systematic evaluation for chronic CNS dosing.

Additionally, Dr. Yu says they do not yet have an explanation for the gap between the near-complete early response and the substantial but partial reduction after resuming via ICV. He adds that the change in route, dose, age, and developmental window are all confounding factors.

“And the deepest question is whether seizure control translates into neurodevelopmental gain — for a disease beginning in the first days of life, what can be recovered after months of uncontrolled seizures remains unknown. Answering it could need longer follow-up, better outcome measures, or earlier intervention than we have,” he says.

Related work and collaboration

Other researchers are also looking into how ASO-based therapies could treat KCNT1-related epilepsy. A 2022 study published in JCI Insight by Steve Petrou and colleagues (2) tested a gene-silencing ASO in a mouse model carrying a KCNT1 variant. The mice had the same frequent, debilitating seizures and developmental delays seen in patients. The authors state that after a single ICV injection of the gapmer ASO in symptomatic mice, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared with mice treated with a control ASO (2); members of the Petrou lab were authors on Dr. Yu’s report (1).

Dr. Yu says his team’s findings extended this into patients: “the seizure reductions we saw were rapid and, at their peak, near-complete — more pronounced than the initial pharmacologic approaches achieved — though, unlike the prior preclinical work, accompanied by a serious adverse event that the animal studies had not predicted.”

In terms of advancing research, he says some of the most important steps are already underway, including their collaboration with Helene Tran and Servier on the KANDLE trial, which is currently recruiting participants for its second-generation anti-KCNT1 ASO.

“This is an example of the sort of academic-to-industry handoff we hope these programs can enable, and one we did not plan for at the outset,” he says.

A complementary modality has also reached the clinical trial phase — Actio’s KYRON Phase 1b/2 trial of ABS-1230, a small-molecule, oral KCNT1 inhibitor.

“Beyond what is underway, I would invest in two things: infrastructure for earlier intervention, since EIMFS begins in the first days of life and earlier diagnosis could calm seizures before significant brain injury; and the shared CNS ASO safety infrastructure that today exists only informally — a harmonized adverse-event registry and real-time pharmacovigilance,” says Yu.

Collaboration with the Kaczmarek and Smith labs was foundational, Dr. Yu says, as their voltage-clamp recordings in patient iPSC-derived neurons defined the gain-of-function physiology they were targeting and provided critical evidence that valeriasen could normalize it.

More broadly, he hopes to see this approach tested in other developmental epilepsies caused by gain-of-function channelopathies, as the marked seizure reduction makes a strong case for carrying the template to genes well beyond KCNT1. The experience has already influenced monitoring practices in other CNS ASO programs.

The future of KCNT1 ASOs: earning trust and sharing knowledge

Although the trial involved only two patients, it offers a clear demonstration that antisense oligonucleotide therapy can rapidly alter the course of a severe developmental epilepsy driven by a single gene. At the same time, the unexpected development of hydrocephalus underscores the challenges of translating genetic therapies from the laboratory to the clinic, where safety is equally important as efficacy.

For families affected by KCNT1-related epileptic encephalopathy, the study provides both hope and caution. As researchers refine dosing strategies, investigate the mechanisms behind these adverse events, and continue ongoing clinical trials, the work represents an important step toward personalized treatments for rare neurological diseases.

These programs turn not only on the molecule but on how they are run — careful monitoring, a willingness to report harms as plainly as benefits, and genuine partnership with the families who take the risk alongside us,” Dr. Yu says. “We have to keep earning that trust, and one way is to turn setbacks into shared knowledge, so the next team inherits what the last one learned. That will do as much for the field as any single method we could hand off.”

*View the full Nature Medicine article for primary data, exact dosing/timing, imaging details, adverse-event tables, and statistical analyses.

References:

1. Nakayama T, El Achkar CM, Burbano LE, Quraishi IH, Wu J, Li M, Asami Y, Golinski SR, Sherrill E, Goodlett BD, de Gusmao CM, Friedman DA, Lentucci C, Suslovitch V, Riccardi O, Faour KNW, Kuniholm A, Soucy Verran A, Coffman S, Ahtam B, Zhao B, Chin DH, DiDonato RL, Hu CA, Lopez E, Hills S, Maljevic S, Tran H, Bush LW, Grant PE, Madsen JR, Smith RS, Kaczmarek LK, Berde CB, Yu TW. Antisense oligonucleotide-mediated knockdown therapy in two infants with severe KCNT1 epileptic encephalopathy. Nat Med. 2026 Apr;32(4):1411-1420. doi: 10.1038/s41591-026-04314-9. Epub 2026 Apr 14. PMID: 41981306; PMCID: PMC13099374.
2. Burbano LE, Li M, Jancovski N, Jafar-Nejad P, Richards K, Sedo A, Soriano A, Rollo B, Jia L, Gazina EV, Piltz S, Adikusuma F, Thomas PQ, Kopsidas H, Rigo F, Reid CA, Maljevic S, Petrou S. Antisense oligonucleotide therapy for KCNT1 encephalopathy. JCI Insight. 2022 Dec 8;7(23):e146090. doi: 10.1172/jci.insight.146090. PMID: 36173683; PMCID: PMC9746904.

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