Channelopathies in Epilepsy: from Precision Medicine to Gene Therapy

Abstract

Epilepsy is a common and debilitating neurological disease with a significant genetic component. Inherited or de novo mutations in ion channels resulting in periodic network hyperexcitability is a major cause of epileptogenesis. Understanding of the genetic etiology of epilepsy opens up the avenue of personalized treatment. A range of precision medications are designed to target the defective ion channels, with varied effects. In addition, the underlying mechanisms of channelopathies can also be addressed by gene therapy. Expression of mutated ion channel genes can be regulated via gene replacement or gene silencing approaches, including viral vector-mediated gene replacement and antisense oligonucleotides. Aside from directly compensating of ion channel dysfunction, another strategy of gene therapy involves the overexpression of certain ion channels to modulate neuronal excitability, which particularly targets focal epilepsies. In line with the paroxysmal nature of epileptic seizures, optogenetic and chemogenetic approaches, which permits conditional activation of gene products can be particularly beneficial. The ideal gene therapy to treat genetic epilepsies and channelopathies would be in vivo gene editing, making precise gene modifications to correct mutations harbored by each individual. Advances in CRISPR- Cas technology has brought the idea closer to reality, yet technical and ethical concerns surround its therapeutic application.