Zebrafish

With recent advances in our understanding of the genetic basis for many epilepsies, hope for curative treatments and effective prevention has increased.  Unfortunately, this information has not resulted in significant clinical advances and where new drugs have emerged, the average cost of research and development for each new drug is estimated at greater than $800 million.  To approach this challenge from a different direction, we leverage the distinct advantages offered by a simple vertebrate - zebrafish (Danio rerio) - as a template for a genetically tractable epilepsy model compatible with rapid, cost-effective and high-throughput drug screening.  Our work with zebrafish began over 20 years ago with the first adaption of acquired seizure protocols (PTZ, pilocarpine, heat, etc.) and has progressed to include stable mutant lines generated with state-of-the-art gene editing technologies.  Drug discovery efforts have led to "aquarium-to-bedside" success with our identifications of Fenfluramine, Lorcaserin and Clemizole in a zebrafish model for Dravet Syndrome.

Current projects in the laboratory include (i) CRISPR-Cas9 editing to generate new zebrafish lines representing all human genetic forms of epilepsy (Epilepsy Zebrafish Project, EZP), (ii) phenotype-based drug discovery, (iii) high-speed imaging studies to deconstruct the neuronal networks responsible for seizure generation and propagation and (iv) advanced machine-learning based approaches to behavioral phenotyping.  Together, a zebrafish-based platform offers a form of "personalized medicine" with the potential to uncover new therapies for a wide range of genetic epilepsies.