An update on the novel methods for the discovery of antiseizure and antiepileptogenic medications: where are we in 2024?

ABSTRACT

Introduction

Despite the availability of around 30 antiseizure medications, 1/3 of patients with epilepsy fail to become seizure-free upon pharmacological treatment. Available medications provide adequate symptomatic control in two-thirds of patients, but disease-modifying drugs are still scarce. Recently, though, new paradigms have been explored.

Areas covered

Three areas are reviewed in which a high degree of innovation in the search for novel antiseizure and antiepileptogenic medications has been implemented: development of novel screening approaches, search for novel therapeutic targets, and adoption of new drug discovery paradigms aligned with a systems pharmacology perspective.

Expert opinion

In the past, worldwide leaders in epilepsy have reiteratively stated that the lack of progress in the field may be explained by the recurrent use of the same molecular targets and screening procedures to identify novel medications. This landscape has changed recently, as reflected by the new Epilepsy Therapy Screening Program and the introduction of many in vitro and in vivo models that could possibly improve our chances of identifying first-in-class medications that may control drug-resistant epilepsy or modify the course of disease. Other milestones include the study of new molecular targets for disease-modifying drugs and exploration of a systems pharmacology perspective to design new drugs.

KEYWORDS:

• Antiepileptogenic drugs
• antiseizure medications
• disease-modifying drugs
• drug discovery
• epilepsy
• epileptogenesis
• network pharmacology
• systems pharmacology

Article highlights

• Most current antiseizure medications have not demonstrated antiepileptogenic or disease-modifying activity, but rather act as symptomatic treatments that fail to control seizures in approximately one third of patients.

• In the last decade, various innovative approaches for the identification of superior and truly antiepileptic therapies have been incorporated, as embodied by the NINDS Epilepsy Therapy Screening Program.

• Chronic animal models of epilepsy and hyperexcitability have so far failed to show predicted validity, as reflected by disappointing clinical trials of drug candidates that had shown promise in such models.

• Human brain slices, organotypic slice cultures, and brain organoids and spheroids may solve some of the issues of animal models in the short- or mid-term, mitigating bioethical concerns and allowing high throughput in models with high biological context.

• The systems pharmacology paradigm has recently been tested at both the preclinical and clinical level.

Declaration of interest

The authors are members of the Argentinean National Council of Scientific and Technical Research Council (CONICET) and researchers at the National University of La Plata (UNLP). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors are members of the Argentinean National Council of Scientific and Technical Research Council (CONICET) and are researchers at the National University of La Plata (UNLP). They authors thank ApoyoDravet and FONCyT’s PICT 2019-1075 for their financial support.