KCNT1-Targeting Antisense Oligonucleotide Reduces Seizures but May Cause Hydrocephalus

A study published in Nature Medicine on April 14, 2026, reports that an experimental antisense oligonucleotide (ASO) therapy significantly reduced seizure frequency and intensity in two infants with a severe form of KCNT1-related epileptic encephalopathy. However, the treatment was also associated with the development of hydrocephalus, a condition involving excess fluid buildup in the brain, in both patients.

The patients involved in the study were two 2-year-old females carrying the KCNT1 p.R474H variant, which is identified as a severe and recurrent pathogenic variant. The researchers utilized a non-allele-specific, KCNT1-targeting ASO, specifically the lead ASO KT777, delivered intrathecally via lumbar puncture.

Understanding KCNT1-Related Encephalopathy

KCNT1-related epileptic encephalopathy, also known as epilepsy of infancy with migrating focal seizures (EIMFS) or early infantile 14 (EIEE14), is described as one of the most severe epilepsy syndromes. Up to 50% of patients with EIMFS have de novo pathogenic variants in the KCNT1 gene.

The KCNT1 gene encodes a sodium-activated potassium channel known as Slack, SLO2.2, or KNa1.1. This channel is widely expressed in neurons throughout the central nervous system and is responsible for modulating neuronal firing patterns and excitability.

Pathogenic variants in KCNT1 lead to overactive Slack channels. According to the research, these variants can boost total neuronal potassium currents by up to 40%, which drives cortical hyperexcitability and results in seizures.

Treatment Mechanism and Clinical Outcomes

Traditional treatments for these disorders have largely been symptomatic, focusing on controlling seizures without addressing the underlying genetic cause. ASO therapy represents a precision medicine approach designed to target the RNA directly to address the root cause of the disease.

The experimental therapy employed a knockdown strategy to reduce KCNT1 levels. While this approach led to a significant reduction in the intensity and frequency of seizures for the two infants, it also triggered severe adverse events.

Both patients developed ventricular enlargement or hydrocephalus following the intrathecal administration of the ASO. In one instance, this complication prompted a redirection of goals of care.

The second patient required a shunt to drain the accumulated fluid and subsequently stopped the ASO treatment.

Broader Implications for ASO Therapies

The occurrence of hydrocephalus in this study points to a potential monitorable toxicity associated with some intrathecal antisense oligonucleotides. This risk is not isolated to KCNT1-targeting therapies.

Other reported instances of hydrocephalus related to ASO treatments include:

• Three patients in a Roche clinical trial for an experimental antisense drug targeting Huntington’s disease.
• Some patients receiving nusinersen.
• Patients treated with valeriasen, an ASO against the KCNT1 gene developed by Boston Children’s Hospital, where one patient passed away after developing severe hydrocephalus.

Medical researchers note that determining whether fluid buildup is caused by the drug or the underlying neurological disease can be difficult, as hydrocephalus is not uncommon in people with various neurological conditions.

Therapeutics that use RNA-targeting molecules are well positioned to directly address the underlying cause of DEE, including seizures and comorbid pathologies.

JCI

While previous studies in homozygous mouse models indicated that ASO-mediated reduction of Kcnt1 was safe and had a disease-modifying effect, the human clinical results highlight a critical tension between therapeutic efficacy and safety.

The findings underscore the necessity of careful monitoring for ventricular enlargement in patients receiving intrathecal ASO therapies for neurodevelopmental disorders.