PubMed: Approaches for the discovery of drugs that target K Na 1.1 channels in <em>KCNT1</em>-associated epilepsy

Expert Opin Drug Discov. 2022 Nov 21. doi: 10.1080/17460441.2023.2150164. Online ahead of print.

ABSTRACT

INTRODUCTION: There are approximately 70 million people with epilepsy and about 30% of patients are not satisfactorily treated. A link between gene mutations and epilepsy is well documented. A number of pathological variants of KCNT1 gene (encoding the weakly voltage-dependent sodium-activated potassium channel – KNa 1.1) mutations has been found. For instance, epilepsy of infancy with migrating focal seizures, autosomal sleep-related hypermotor epilepsy or Ohtahara syndrome have been associated with KCNT1 gene mutations.

AREAS COVERED: Several methods for studies on KNa 1.1 channels have been reviewed – patch clamp analysis, Förster resonance energy transfer spectroscopy and whole exom sequencing. The authors also review available drugs for the management of KCNT1 epilepsies.

EXPERT OPINION: The current methods enable deeper insights into electrophysiology of KNa 1.1 channels or its functioning in different activation states. It is also possible to identify a given KCNT1 mutation. Quinidine and cannabidiol show variable efficacy as add-on to baseline antiepileptic drugs so more effective treatments are required. A combined approach with the methods shown above, in silico methods and the animal model of KCNT1 epilepsies seems likely to create personalized treatment of patients with KCNT1 gene mutations.

PMID:36408599 | DOI:10.1080/17460441.2023.2150164