Therapies

Objective: Central to the development of novel antiseizure medications (ASMs) is testing of antiseizure activity in preclinical models. Although various well-established models exist, their predictive validity across the spectrum of clinical epilepsies has been less clear. We sought to establish the translational concordance of commonly used preclinical models to define models with the highest predictive clinical validity for focal onset seizures (FOS).

The inhibitory neurotransmitter, GABA, is implicated in a number of seizure disorders. As a pentameric iontropic channel, GABA-A is a well-established therapeutic target to modulate inhibitory tone in the brain and provide seizure suppressive effects. However, many of the GABA-A modulators, such as benzodiazepines and barbiturates, are associated with significant sedative effects that reduce their suitability for chronic use in people with epilepsy. New treatments that can modulate the GABA-A receptor without sedating effects are thus in strong demand. This new study characterized the in vivo therapeutic response profile the the novel GABA-A positive allosteric modulator, ENX-101. Results suggest that this compound is well-tolerated and demonstrates minimal sedating effects at anticonvulsant doses, warranting further in vivo preclinical study and potential clinical evaluation in people with focal onset seizures.  

Soticlestat is a first-in-class therapy under clinical development for pediatric epilepsy, with a particular focus on Lennox Gastaut and Dravet Syndromes. This preclinical study evaluated the anticonvulsant and disease-modifying potential in a mouse model of infection-induced acquired seizures. Notably, soticlestat demonstrated robust suppression of seizure presentation in vivo. 

We employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify a novel antiseizure medicine, chlorothymol. This study establishes a new screening approach across preclinical models.