# Targeted Gene and Genome-Editing Strategies for Epilepsy: Experimental Advances and Translational Challenges

## TL;DR

This paper reviews how gene therapy and genome editing could offer new treatments for epilepsy by targeting its molecular causes, despite challenges in translating these approaches to patients.

## Contribution

The paper provides a critical review of recent advances and challenges in applying gene and genome-editing strategies for epilepsy.

## Key findings

- CRISPR-based tools allow gene regulation in neurons without DNA breaks, offering safer options for epilepsy treatment.
- Viral and non-viral delivery systems have enabled precise manipulation of neuronal and glial function in preclinical models.
- Translational challenges include cell-type-specific delivery and long-term safety in the epileptic brain.

## Abstract

Epilepsy affects more than 50 million individuals worldwide, and approximately one-third of patients remain refractory to existing antiseizure medications. Advances in gene therapy and genome editing have opened new possibilities for disease-modifying interventions that directly target the molecular and circuit-level mechanisms underlying epileptogenesis. Recent progress in central nervous system tropic viral vectors, non-viral delivery systems, and programmable genome-editing technologies has enabled precise manipulation of neuronal and glial function in preclinical epilepsy models. Strategies range from restoration of haploinsufficient genes implicated in monogenic epilepsies, such as SCN1A in Dravet syndrome, to modulation of neuronal excitability through engineered ion channels, neuropeptides, and astrocyte-based approaches. In parallel, CRISPR-derived platforms, including transcriptional activation and repression systems, base editing, and prime editing, offer new avenues for regulating gene expression in post-mitotic neurons without introducing double-strand DNA breaks. Despite these advances, significant translational challenges remain, including efficient and cell-type-specific delivery, long-term safety, and the risk of network-level side effects in the epileptic brain. This review critically examines recent gene therapy and genome-editing approaches for epilepsy, highlights key technological and biological barriers to clinical translation, and discusses emerging strategies that may enable durable and targeted treatments for drug-resistant epilepsies.