Gene therapy for epilepsy: From SCN1A to broadened therapeutic horizons (Review)

Genetic epilepsy, for which the molecular mechanisms are relatively well defined in numerous monogenic forms, represents an attractive model for the transition from symptomatic seizure control to mechanism‑driven correction. However, gene therapy strategies differ in their mechanisms of action, adaptability to specific mutations and translational maturity, making rational selection of interventions based on variant‑specific functional consequences an important clinical challenge. The present review examined five nucleic acid‑based therapeutic strategies, namely gene supplementation, enhancement of endogenous gene expression, gene silencing, DNA editing and RNA editing, for major causative genes, using mutation‑specific functional consequences [loss‑of‑function (LOF) vs. gain‑of‑function] as the primary framework for therapeutic decision‑making. The mechanisms and suitability of each approach are analysed, and their performance in terms of cell‑type specificity, delivery vectors and safety is evaluated by integrating evidence from animal models, induced pluripotent stem cell‑derived neurons and organoids and clinical trials. The present review also summarised key translational barriers, including vector cargo constraints, blood‑brain barrier penetration, off‑target and immune‑associated risks, therapeutic dosing windows and the timing of developmental intervention. Antisense oligonucleotides and regulatory adeno‑associated viral approaches, supported by mature delivery platforms and manageable safety profiles, have progressed furthest towards clinical validation. Endogenous gene activation strategies, such as CRISPR activation, offer a gene replacement‑free approach for LOF disorders but remain preclinical. DNA and RNA editing, while potentially capable of durable disease modification, require further evidence on delivery efficiency and long‑term homeostatic safety. Gene therapy for genetic epilepsy is undergoing a key transition from proof‑of‑concept studies to individualised clinical application. Future progress will depend on integrating personalised intervention design, multi‑target therapeutic combinations, artificial intelligence‑assisted sequence optimisation and standardised translational models, with the potential to drive a paradigm shift from seizure suppression to mechanistic correction.

Abstract from PubMed (PMID 42992560). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.