Development of a preclinical screening platform for clinically relevant therapy of Dravet syndrome

Abstract

AbstractBackgroundPatients with drug-resistant epilepsy, including Dravet syndrome (DS), are frequently prescribed multiple antiseizure medications (ASMs). Nevertheless, people with DS often have inadequate seizure control, and there is an ongoing unmet clinical need to identify novel therapeutics. As a proof-of-principle study to further validate and characterize theScn1aA1783V/WTmouse model and identify a drug screening paradigm with face, construct, and predictive value, we assessed the efficacy of subchronic administration of stiripentol add-on to clobazam and valproic acid at clinically relevant doses using theScn1aA1783V/WTmouse model.MethodsWe evaluated the efficacy of STP add-on to CLB and VPA using hyperthermia-induced and video-EEG monitoring of spontaneous seizure tests following a 14-day treatment. VPA was delivered via osmotic minipump, while STP and CLB were administered via food pellets delivered through automatic feeders. Bioanalytical assays were performed to evaluate drug concentrations in plasma and brain using liquid chromatography-tandem mass spectrometry.ResultsSTP, CLB, N-desmethylclobazam, and VPA all yielded plasma concentrations within the human therapeutic plasma concentrations range. STP added to CLB and VPA significantly elevated the seizing temperatures in the hyperthermia-induced seizure assay. CLB, VPA, and STP coadministration significantly reduced spontaneous seizure frequency compared to CLB and VPA combined.SignificanceThis research lays the groundwork for exploring effective add-on compounds to CLB and VPA in treating DS. The study further highlights the utility of theScn1aA1783V/WTmice in discovering therapies for DS-associated pharmacoresistant seizures.Key pointsIntegrating pharmacokinetic studies to guide the selection of doses in preclinical studies to achieve target concentrations comparable to the human therapeutic range is crucial in successfully translating animal drug development studies to clinical use.STP add-on to CLB and VPA significantly reduced spontaneous seizure frequency inScn1aA1783V/WTmice.A triple-drug polytherapy approach that mimics the clinical treatment paradigm will be an essential preclinical drug screening strategy for identifying novel investigational compounds for Dravet syndrome.