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

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.