Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy

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-exome 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.

KEYWORDS:

• KCNT1 epilepsy
• patch clamp
• Förster resonance energy transfer spectroscopy
• whole exome sequencing
• quinidine
• cannabidiol
• seizures

Article highlights

• Pathological variants of KCNT1 gene are responsible for mutations in the weakly voltage-dependent sodium-activated potassium channel - KNa 1.1.

• KCNT1 mutation-dependent epileptic disorders include epilepsy of infancy with migrating focal seizures, autosomal dominant nocturnal frontal lobe epilepsy, autosomal sleep-related hypermotor epilepsy, Ohtahara syndrome, West syndrome, and Lennox-Gastaut syndrome.

• Existing therapies of KCNT1 epilepsies with antiepileptic drugs have been not efficient.

• Quinidine or cannabidiol exert variable protective effects in KCNT1 epilepsies.

• KNa 1.1 channels may be studied with the use of patch clamp analysis, Förster resonance energy transfer spectroscopy and whole-exome sequencing.

Combined approach with these methods, in silico studies and an animal model of KCNT1 childhood epilepsy may provide valuable drugs for the successful management of patients with KCNT1 gene variants.

Declaration of interest

SJ Czuczwar is the recipient of an unrestricted grant from GlaxoSmith Kline. He has also received financial support from Bayer, GlaxoSmithKline, Janssen, Novartis, Sanofi-Aventis for lecturing. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or mending, or royalties apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.