Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies

Abstract

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy—particularly of childhood onset—experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

“…Furthermore, mouse models allow for the identification and validation of potential biomarkers associated with monogenic epilepsy, which can be instrumental in diagnosing the condition, predicting its progression, and monitoring an individual's response to treatment [40]. Lastly, mouse models provide a preclinical testing platform for evaluating novel therapies, such as gene therapy, targeted drugs, and neurostimulation techniques, before their translation into clinical trials [41]. These avenues highlight the significant role of mouse models in furthering our knowledge and improving therapeutic approaches in the field of monogenic epilepsy.…”

A Comprehensive Review of Emerging Trends and Innovative Therapies in Epilepsy Management

“…In the context of epilepsy, gene therapy holds the potential to address the underlying genetic abnormalities that give rise to seizure disorders [ 192 ]. By targeting specific genes associated with epilepsy, gene therapy aims to restore normal cellular function and inhibit seizure generation, providing a promising avenue for the development of novel and more targeted epilepsy treatments [ 40 , 186 , 193 ].…”

Genethormonal Outlook of Epilepsy: A Case Report Associated with Catamenial Epilepsy

“…Basic treatment options available include the ketogenic diet and vagus nerve stimulation, but with very few benefits. [6] Originally, a mutation in SLC2A1 was responsible for the expression of type 1 glucose transporter in the blood-brain barrier, causing hypoglycemia and seizures. This can be cured by providing ketogenic supplements.…”

“…[41] Other treatments include gene replacement therapy (GRT) and genetic substrate reduction therapy to reduce the increased expression or increase in the required protein synthesis. [6] People with focal epilepsy, particularly temporal lobe epilepsy, are better candidates for gene therapy. GRT includes the transport of genetic material directly into the brain, but this might be difficult because of the presence of the blood-brain barrier, so cell transplantation via non-pathogenic viral vectors is feasible.…”

“…[2] Genetic epilepsies are characterized by a prompt seizure due to gene variations or mutations causing improper development of certain parts of the brain or loss of neuronal connectivity. [6] Around 70-80% of epilepsy cases are genetically originated and the remaining 20-30% are due to acquired causes. [7] large cross-sectional study has been done to lay an understanding of risk factors associated with epilepsy using National Health And Nutrition Examination Surveys (NHANES) data.…”