Abstracts

Rationale: Despite the advent of newer medications, 30% to 40% of epileptic patients are refractory to any known drugs and continue to have unremitting recurrent seizures and attendant life-long cognitive, behavioural and mental health problems. The continued persistence of this refractory population suggests that novel approaches to anti-seizure drug discovery are needed to uncover new drugs with unexpected mechanisms of action.

Methods: Here, we describe a metabolism-based drug-screening platform (termed MitoRead) that harnesses the power of organoids, zebrafish genetics and the measurement of whole animal bioenergetics to unbiasedly uncover new druggable targets that might confer anti-seizure properties based on the improvement in mitochondrial function.

Results: We have screened nearly 2,000 repurposed compounds for which the drug target is already known and identified dozens of new anti-seizure targets. We have validated several of these targets using pharmacological and knockdown approaches in Scn1a-mutant zebrafish and mice, including assaying hyperthermia-induced seizures and video-EEG. Our lead program is in hit-to-lead optimization for a novel compound that displays a unique mechanism of action for Dravet syndrome. We are rapidly transitioning the MitoRead platform from zebrafish to brain organoids and can now measure metabolic changes in Dravet patient-derived organoids. For the first time we show that brain organoids from Dravet individuals possess unique metabolic signatures that can be used for a personalized medicine drug screen. Currently, we are testing the utility of the MitoRead platform in organoids using known antiseizure drugs._x000D_
Conclusions: Combined, our metabolism-based approach to identifying unexpected druggable pathways and targets with novel mechanism of action represents a new direction for the discovery of novel therapeutics for intractable epilepsy.

Funding: Not applicable