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

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 in vivo 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.

KEYWORDS:

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

Article highlights

• Numerous ‘traditional’ animal seizure and epilepsy models have proven validity for translating effective investigational compounds into clinically impactful therapies, including maximal electroshock and pentylenetetrazol.

• Increased integration of non-traditional syndrome-specific models associated with epilepsy syndromes has led to several clinically approved treatments for epilepsy in the 21^st century.

• Reliance on traditional mammalian seizure models in parallel with animal genetic models of specific hyperexcitable states may lead to even more therapeutic innovation in the coming decades.

• Rodent models that are defined by a drug-resistant phenotype or are evoked by more translationally relevant neurological insults, such as brain infection, may lead to novel therapeutic targets and treatments.

• Syndrome-specific seizure and epilepsy models are going to play a greater role in epilepsy drug discovery despite their increased costs and resource demands because they are more likely to uncover novel therapeutic opportunities.

Declaration of interest

M Barker-Haliski has received research support from Ovid, Janssen Pharmaceuticals, Biogen and Jazz Pharmaceuticals. Dr. Hawkins has received research support from Ovid, Neurocrine, and Praxis Pharmaceuticals and is a paid consultant for Takeda Pharmaceuticals. 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 funded by the National Institutes of Health through the National Institute of Neurological Disorders and Stroke [grant no. R61NS126626] and the National Institute of Aging [grant no. R01AG067788].