2026-04-30 ノースウェスタン大学
Getty Images
＜関連情報＞
- https://news.northwestern.edu/stories/2026/4/treatment-of-rare-childhood-epilepsy-could-begin-before-birth
- https://www.nature.com/articles/s41467-026-72334-7
- https://medibio.tiisys.com/180195/
重度の小児てんかんおよび早期死亡に関連する出生前カリウムチャネルを標的としたRNA療法 RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death
Sean R. Golinski,Karla Soriano,Alex C. Briegel,Madeline C. Burke,Sheng Tang,Gemma L. Carvill,Emma Sherrill,Claudia Lentucci,Timothy W. Yu,Tojo Nakayama,Ruilong Hu & Richard S. Smith
Nature Communications Published:29 April 2026
DOI:https://doi.org/10.1038/s41467-026-72334-7 Unedited version
Abstract
Dysfunction of the sodium-activated potassium channel KNa1.1 (encoded by KCNT1) is associated with a severe neurodevelopmental condition characterized by frequent seizures (up to hundreds per day), treatment resistance, and increased mortality during childhood. Yet, recent progress with an RNA therapy targeting KCNT1 offers clinical promise1. We characterize the early developmental onset of KNa1.1 channels in prenatal and neonatal brain tissue, establishing a timeline for pathophysiology and a window for therapeutic intervention. Using patch-clamp electrophysiology, we observe functional prenatal KNa1.1 conductance that is developmentally regulated. In excitatory and inhibitory neurons derived from a child’s induced pluripotent stem cells with a KCNT1 pathogenic variant (p.R474H), we detect gain-of-function K+ currents. We use an antisense oligonucleotide RNA therapy developed for two individuals with the p.R474H variant—which results in dramatic reductions in seizure occurrence and severity1—to profile cellular neurophysiology in patient-derived excitatory and inhibitory neurons. We observe a knockdown of p.R474H gain-of-function K+ currents, resulting in a stimulation-dependent change in spiking output in patient-derived induced excitatory and inhibitory neurons. In mid-gestation primary human neurons, ASO knockdown suppresses current-evoked firing, suggesting a potential early therapeutic target before the onset of infantile encephalopathy.
