Innovative drug discovery strategies in epilepsy: integrating next-generation syndrome-specific mouse models to address pharmacoresistance and epileptogenesis

Melissa Barker-Haliski*, Nicole A. Hawkins

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

Introduction: Although there are numerous treatment options already available for epilepsy, over 30% of patients remain resistant to these antiseizure medications (ASMs). Historically, ASM discovery has relied on the demonstration of efficacy through the use of ‘traditional’ acute invivo seizure models (e.g. maximal electroshock, subcutaneous pentylenetetrazol, and kindling). However, advances in genetic sequencing technologies and remaining medical needs for people with treatment-resistant epilepsy or special patient populations have encouraged recent efforts to identify novel compounds in syndrome-specific models of epilepsy. Syndrome-specific models, including Scn1a variant models of Dravet syndrome and APP/PS1 mice associated with familial early-onset Alzheimer’s disease, have already led to the discovery of two mechanistically novel treatments for developmental and epileptic encephalopathies (DEEs), namely cannabidiol and soticlestat, respectively. Areas covered: In this review, the authors discuss how it is likely that next-generation drug discovery efforts for epilepsy will more comprehensively integrate syndrome-specific epilepsy models into early drug discovery providing the reader with their expert perspectives. Expert opinion: The percentage of patients with pharmacoresistant epilepsy has remained unchanged despite over 30 marketed ASMs. Consequently, there is a high unmet need to reinvent and revise discovery strategies to more effectively address the remaining needs of patients with specific epilepsy syndromes, including drug-resistant epilepsy and DEEs.

Original languageEnglish (US)
Pages (from-to)1099-1113
Number of pages15
JournalExpert Opinion on Drug Discovery
Volume19
Issue number9
DOIs
StatePublished - 2024

Keywords

  • Alzheimer’s
  • cannabidiol
  • Developmental and epileptic encephalopathy
  • lamotrigine-resistant corneal kindled mouse
  • soticlestat
  • Theiler’s virus encephalitis model

ASJC Scopus subject areas

  • Drug Discovery

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