Are Genetic Therapies for Epilepsy Ready for the Clinic?

Abstract

In recent years, there has been a significant increase in preclinical studies to test genetic therapies for epilepsy. Some of these therapies have advanced to clinical trials and are being tested in patients with monogenetic or focal refractory epilepsy. This article provides an overview of the current state of preclinical studies that show potential for clinical translation. Specifically, we focus on genetic therapies that have demonstrated a clear effect on seizures in animal models and have the potential to be translated to clinical settings. Both therapies targeting the cause of the disease and those that treat symptoms are discussed. We believe that the next few years will be crucial in determining the potential of genetic therapies for treating patients with epilepsy.

Viral Vector-Based Gene Therapy for Epilepsy: What Does the Future Hold?

“…Gene therapy approaches for epilepsy can be divided into two broad categories: those targeting the gene defect, for genetic forms of the disease; and those targeting mechanism(s) of seizure generation [ 13 ]. In both cases, different gene therapy approaches have been developed, based on anti-sense oligonucleotides, RNA interference, and viral vectors.…”

“…In both cases, different gene therapy approaches have been developed, based on anti-sense oligonucleotides, RNA interference, and viral vectors. In this opinion paper, while referring the reader to other articles discussing other approaches [ 13 , 14 ], we focus on in vivo gene therapies mediated by viral vectors. For such an approach to be successful, many issues should be considered and addressed, for example, optimization of the natural ability of viruses to transfer genetic material into target cells; production of clinical-grade vectors; targeting of specific cell populations in a highly heterogeneous environment; long-lasting and modulated expression of therapeutic genes; and safety.…”

“…Altogether, gene therapy is now emerging as a promising therapeutic strategy for many diseases, including diseases that may not have a genetic cause, such as Parkinson's disease and Alzheimer's disease [12]. Gene therapy approaches for epilepsy can be divided into two broad categories: those targeting the gene defect, for genetic forms of the disease; and those targeting mechanism(s) of seizure generation [13]. In both cases, different gene therapy approaches have been developed, based on anti-sense oligonucleotides, RNA interference, and viral vectors.…”

Response to Singh et al. 2023: It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade

“…Our review is a hypothesis and, like any hypothesis, certainly requires further validation, but the main rationale was to propose therapeutic approaches that can be tested in PWE in the near future. The preventative approaches we suggested can be considered as potential temporizing treatments before more definitive personalized medicine approaches, such as gene‐based therapy, can be developed (see Street et al 25 for review). Hopefully, these will prove to be effective in specific genetic epilepsy cases, such as the SCN1A mutations in Dravet syndrome, but several other genetic mutations are also associated with high incidences of SUDEP 26–29 .…”