Allele-agnostic KCNH1 suppression rescues gain-of-function developmental epileptic encephalopathy

KCNH1 suppression with a gapmer ASO normalized neuronal network dysfunction and reduced seizures in Kcnh1-R357Q knock-in mice, restoring survival to near-normal levels.

• Why it matters: Gain-of-function KCNH1 variants cause developmental and epileptic encephalopathies, yet allele-agnostic suppression is plausible because KCNH1 loss is tolerated in humans and mice.
• What they did: The team designed a KCNH1-targeting gapmer ASO and tested it in human iPSC-derived neurons carrying I494V or G375R, then in a new Kcnh1-R357Q knock-in mouse model.
• The result: ASOs lowered KCNH1 expression in control neurons without disrupting network activity, but normalized network dysfunction in both mutant genotypes and, in vivo, significantly reduced seizure burden after a single treatment.

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