Therapeutic Potential of ASO-Mediated KCNT1 Knockdown in KCNT1 Epileptic Encephalopathy

KCNT1-related epileptic encephalopathy, including Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), is a severe neurodevelopmental disorder associated with refractory seizures, profound neurologic impairment, and premature death. It is caused by de novo genetic variants in KCNT1 which alter the function of Slack, an evolutionarily conserved sodium-gated potassium channel that modulates neuronal firing patterns and excitability. Pathogenic KCNT1 variants lead to overactive Slack channels, boosting total neuronal potassium currents by up to 40%, driving cortical hyperexcitability and causing seizures. Here we investigate antisense oligonucleotide (ASO)-mediated KCNT1 knockdown as a therapeutic strategy for patients with EIMFS. Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting ASO by lumbar puncture in two patients with KCNT1 p.R474H, a severe, recurrent pathogenic variant, led to a significant reduction in seizure frequency and intensity, supporting the potential efficacy of suppression of KCNT1 expression as a therapeutic strategy for EIMFS. However, investigational treatment was also associated with development of ventricular enlargement or hydrocephalus in both patients, prompting in one case redirection of goals of care. This finding was not clearly related to EIMFS itself, drawing attention to an important possible toxicity of some intrathecal antisense oligonucleotides.