Early infantile epileptic encephalopathy (EIEE) is a severe brain disorder with poor prognosis and no adequate therapies, characterized by recurrent intractable seizures in newborns and infants. EIEE-causing mutations have been identified in hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), a voltage-gated channel widely expressed in the central nervous system (CNS). Despite the growing number of identified HCN1 variants, the mechanisms by which they alter channel function and contribute to pathogenesis remain poorly understood. Moreover, the lack of isoform-specific and brain-penetrant modulators highlights the urgent need to develop antiepileptic drugs that specifically target HCN1 in the brain. To this end, we combined our expertise in channel biophysics and structural biology to classify a panel of HCN1 variants into four functional classes (I-IV) and to explain their phenotypes in terms of altered molecular mechanisms. This precise knowledge of HCN1 dysfunction led to the identification of appropriate pharmacological treatments for three of the four classes. The identified treatments include peptide tools, nanobodies and small molecules that restore wild-type-like function in mutant HCN1 channels, underscoring the potential of precision medicine approaches tailored to mutation-specific phenotypes. We further validated some of these modulators ex vivo in a knock-in HCN1 mouse model, which closely recapitulates key features of HCN1 dysfunction, effectively rescuing altered intrinsic properties, and excitability of hippocampal CA1 pyramidal neurons. Our work lays the ground for a precision medicine approach to HCN1 epilepsy and provides robust indications and innovative tools to clinicians for the treatment of individual patients.
Moroni et al. (2026) studied this question.