Seizure-suppressor genes: can they help spearhead the discovery of novel therapeutic targets for epilepsy?

ABSTRACT

Introduction

Epilepsies are disorders of neuronal excitability characterized by spontaneously recurrent focal and generalized seizures, some of which result from genetic mutations. Despite the availability of antiseizure medications, pharmaco-resistant epilepsy is seen in about 23% of epileptic patients worldwide. Therefore, there is an urgent need to develop novel therapeutic strategies for epilepsies. Several epilepsy-associated genes have been found in humans. Seizure susceptibility can also be induced in Drosophila mutants, some showing features resembling human epilepsies. Interestingly, several second-site mutation gene products have been found to suppress seizure susceptibility in the seizure genetic model Drosophila. Thus, these so-called ‘seizure-suppressor’ gene variants may lead to developing a novel class of antiseizure medications.

Area covered

This review evaluates the potential therapeutic of seizure-suppressor gene variants.

Expert opinion

Studies on epilepsy-associated genes have allowed analyses of mutations linked to human epilepsy by reproducing these mutations in Drosophila using reverse genetics to generate potential antiseizure therapeutics. As a result, about fifteen seizure-suppressor gene mutants have been identified. Furthermore, some of these epilepsy gene mutations affect ligand-and voltage-gated ion channels. Therefore, a better understanding of the antiseizure activity of seizure-suppressor genes is essential in advancing gene therapy and precision medicine for epilepsy.

KEYWORDS:

• Genetic epilepsy
• gene mutation
• seizure-suppressor gene
• anticonvulsant
• Drosophila

Article highlights

• Epilepsies are complex and heterogeneous disorders of neuronal excitability characterized by spontaneously recurrent seizures, some of which result from genetic mutations.

• Severe and pharmaco-resistant epilepsies often originate from gene mutations.

• Seizure-suppressor genes are modified second mutations that can revert partially or totally the seizure phenotypes of mutants and can be separated genetically, by recombination, from the mutation they suppress.

• Overall review and update of seizure-suppressor gene mutants in Drosophila seizure models

• Expert opinion on using seizure-suppressor gene mutants as an innovative approach to advancing gene therapy and precision medicine for epilepsies.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This manuscript was funded by the National Institute of Alcoholism and Alcohol Abuse under grant R01AA027660 (PN).