Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA

作者：Benjamin J. Andreone, Jennifer S Lin, Jenna Tocci, Matthew L. Rook, Amr Omer, Lauren M. Carito, Chunhua Yang, Hryhoriy Zhoba, Christopher Dejesus, Mariam Traoré, Phensinee Haruehanroengra, Alex Prinzen, Gregory Miglis, Matthew Deninger, Mingwei Li, Taylor Lynch, Bryce Howat, Kelly A. Rogers, Corrie L. Gallant‐Behm, Garth A. Kinberger, Guillermo A. Yudowski, Qingmin Chen, Aimee L. Jackson, Stefan McDonough · 发表于：Epilepsia · 年份：2025 · DOI：10.1111/epi.18278 · 被引用次数：9 · 研究领域：Epilepsy research and treatment、Ion channel regulation and function、Genomics and Rare Diseases

OBJECTIVE: Gain-of-function variants in the KCNT1 gene, which encodes a sodium-activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression of seizures in a genetic mouse model of KCNT1 epilepsy by reducing Kcnt1 transcript with divalent small interfering RNA (siRNA), an emerging variant of oligonucleotide technology developed for the central nervous system. METHODS: The ATL-201 molecule is two identical synthetic double-stranded siRNAs, covalently linked, with 100% nucleotide base pair match to sequence present in both human KCNT1 and mouse Kcnt1 that does not contain any known pathogenic variant. ATL-201 activity was tested in cortical neurons cultured from wild-type mice and in mice homozygous for Kcnt1-Y777H, the mouse ortholog to the human pathogenic KCNT1-Y796H missense variant. Seizures and nest-building behavior were measured in freely behaving Kcnt1-Y777H mice. The number and duration of seizures were measured by electrocorticography in mice dosed with ATL-201 or phosphate-buffered saline in a 6-month durability study and in a 2-month dose-efficacy study. RESULTS: In vitro, ATL-201 reduced KCNT1 transcript from whole-cell lysate and eliminated potassium currents from KCNT1 channels in heterologous expression. ATL-201 also eliminated sodium...