Preprint: antisense suppression of KCNH1 rescues mouse and neuron models of channel gain-of-function epilepsy

What happened

Gain-of-function variants in KCNH1, which encodes the voltage-gated potassium channel Kv10.1, cause developmental and epileptic encephalopathies. Because loss of KCNH1 appears to be tolerated in humans and mice, the authors tested allele-agnostic suppression with a gapmer antisense oligonucleotide (ASO).

Human iPSC-derived neurons carrying the pathogenic variants I494V or G375R shared a hyperpolarised resting membrane potential and abnormal network activity, with largely preserved intrinsic firing. The ASO reduced KCNH1 expression without disrupting network activity in control neurons, and normalised network dysfunction in both mutant genotypes. In a newly generated Kcnh1-R357Q knock-in mouse, which showed severe seizures and early mortality, a single ASO treatment significantly reduced seizure burden and restored survival to near-normal levels.

Why it matters

Distinct variants shared a hyperpolarised resting membrane potential and a network phenotype that the ASO normalised, which supports lowering channel expression as a strategy for gain-of-function channelopathies where partial reduction is tolerated.

Caveats

This is a preprint and has not been peer reviewed. This entry draws on the abstract and a summary of the bioRxiv full text; figures and statistics were not checked in detail. The authors declare relationships with companies (including cofounder roles at NuCyRNA and ENOSIS Therapeutics for one author, and advisory or grant relationships with others) but state that none of the companies were involved in this project. Results are from cultured human neurons and mice; the ASO used in mice is mouse-specific, not a human drug; therapeutic window, durability and long-term safety are not yet studied; no human treatment is reported.