针对与严重儿童癫痫和过早死亡相关的产前富集钾通道的RNA靶向治疗
RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.
摘要(中文译文)
钠激活钾通道K1.1（由KCNT1编码）的功能障碍与一种严重的神经发育性疾病相关，该疾病以频繁癫痫发作（每日可达数百次）、治疗抵抗及儿童期死亡率增加为特征。然而，近期针对KCNT1的RNA治疗进展带来了临床希望。我们表征了K1.1通道在产前及新生儿脑组织中的早期发育出现时间，从而建立了病理生理学的时间线及治疗干预的时间窗口。利用膜片钳电生理技术，我们观察到产前即存在功能性K1.1电导，且受发育调控。在来源于携带KCNT1致病性变异（p.R474H）儿童诱导多能干细胞分化的兴奋性和抑制性神经元中，我们检测到功能获得性K电流。我们使用针对两名携带p.R474H变异个体开发的反义寡核苷酸RNA疗法——该疗法使癫痫发作频率和严重程度显著降低——来分析患者来源兴奋性和抑制性神经元的细胞神经生理学特征。我们观察到p.R474H功能获得性K电流被敲低，导致患者来源诱导兴奋性和抑制性神经元的放电输出发生刺激依赖性改变。在妊娠中期的原代人神经元中，ASO敲低抑制了电流诱发的放电，提示在婴儿脑病发病前存在一个潜在的早期治疗靶点。
Abstract
Dysfunction of the sodium-activated potassium channel K1.1 (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 promise. We characterize the early developmental onset of K1.1 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 K1.1 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 severity-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.
如何引用
AMA
Sean R Golinski, Karla Soriano, Alex C Briegel, Madeline C Burke, Sheng Tang, Gemma L Carvill, et al. RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.. Nature communications. 2026; doi:10.1038/s41467-026-72334-7.
APA
Sean R Golinski, Karla Soriano, Alex C Briegel, Madeline C Burke, Sheng Tang, Gemma L Carvill, et al (2026). RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.. Nature communications. https://doi.org/10.1038/s41467-026-72334-7
GB/T 7714
Sean R Golinski, Karla Soriano, Alex C Briegel, Madeline C Burke, Sheng Tang, Gemma L Carvill, et al. RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72334-7.
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