A precision medicine approach forHCN1Developmental and Epileptic Encephalopathy

Abstract

Pathogenic variants inHCN1causing cation leak result in a severe developmental and epileptic encephalopathy (DEE). Current treatment options for patients withHCN1-DEE are limited and are insufficient to fully address both the seizures and clinical comorbidities of this disorder.Org 34167 is a brain penetrant broad-spectrum HCN channel inhibitor that has completed phase I clinical trials. We used a range of assays at molecular, cellular, network and behavioural levels to explore the potential of Org 34167 as a precision medicine forHCN1-DEE.Org 34167 restored the voltage sensitivity of the DEE HCN1M305Lmutated channel, significantly reducing cation leak. It also restored Ih-mediated ‘sag’, hyperpolarised the resting membrane potential and reduced firing of layer V neurons from the Hcn1M294Lmouse model ofHCN1-DEE, which was engineered based on the HCN1M305Lpathogenic variant. Additionally, Org 34167 reduced neuronal epileptiform activity and restored retinal light sensitivity in these mice, suggesting it may improve both seizures and other clinical comorbidities. However, Org 34167-mediated tremors were noted at therapeutic doses. Org 34167 was also effective at reducing cation leak caused by five additionalHCN1pathogenic variants, suggesting broader utility.Overall, these data demonstrate that a small molecule HCN inhibitor can restore channel and consequent physiological functions, positioning it as a promising precision therapeutic approach forHCN1-DEE.