RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death.
Overview
- Northwestern University, Feinberg School of Medicine,Chicago, IL USA
- Division of Genetics and Genomics, Boston Children’s Hospital,Boston, MA USA
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
No file of the authors' code could be read here: it is described below, and read at its source.
Smith-Lab-Neuro
Availability: 1 check, the latest on 30 September 2026: the link answers (HTTP 200)
- 30 September 2026: the link answers (HTTP 200)
Code availability
See Richard Smith Lab GitHub for Analysis code or access to data. https://
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
No dataset and no data link were found in the paper.
Data availability
Relevant source data are provided within this paper. RNA-sequencing data is available on NCBI Gene Expression Omnibus (GEO) and are available under GEO Series accession GSE297948. The reference resources used in this study include the Genome Reference Consortium Human Build 38 (GRCh38) assembly. See “Source Data” for data series. Source data are provided with this paper.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 30 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 2 keywords, 11 MeSH terms, 1 funder, 62 references.
Cite
This paper
Golinski, S. R., Soriano, K., Briegel, A. C., Burke, M. C., Tang, S., Carvill, G. L., Sherrill, E., Lentucci, C., Yu, T. W., Nakayama, T., Hu, R., & Smith, R. S. (2026). RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death. Nature communications, 17(1), 5864. https://
BibTeX
@article{golinski2026rna
author = {Golinski, Sean R. and Soriano, Karla and Briegel, Alex C. and Burke, Madeline C. and Tang, Sheng and Carvill, Gemma L. and Sherrill, Emma and Lentucci, Claudia and Yu, Timothy W. and Nakayama, Tojo and Hu, Ruilong and Smith, Richard S.},
title = {{RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death}},
journal = {Nature communications},
year = {2026},
month = apr,
volume = {17},
number = {1},
pages = {5864},
publisher = {Nature Publishing Group},
issn = {2041-1723},
doi = {10.1038/
url = {https://
pmid = {42056090},
pmcid = {PMC13333874}
}
RIS
TY - JOUR
AU - Golinski, Sean R.
AU - Soriano, Karla
AU - Briegel, Alex C.
AU - Burke, Madeline C.
AU - Tang, Sheng
AU - Carvill, Gemma L.
AU - Sherrill, Emma
AU - Lentucci, Claudia
AU - Yu, Timothy W.
AU - Nakayama, Tojo
AU - Hu, Ruilong
AU - Smith, Richard S.
TI - RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death
T2 - Nature communications
J2 - Nat Commun
PY - 2026
DA - 2026/
VL - 17
IS - 1
SP - 5864
SN - 2041-1723
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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