Recent discoveries have shown that loss-of-function variants of SCN2A are causal for a number of neurodevelopmental disorders, including autism spectrum disorder (ASD). Given this genetic linkage to disease, our team at the Broad Institute established a drug discovery program to develop small molecule activators of NaV1.2 as a therapeutic strategy for ASD. In this presentation, we will describe the design and establishment of a screening cascade for the identification of modulators of NaV1.2.

We first established a novel primary high-throughput screening (HTS) assay combining electric field stimulation with the detection of membrane potential changes in an NaV1.2 over-expressing cell line. Using this assay, we completed an HTS of nearly 80,000 compounds and identified 378 enhancers of NaV1.2 function. Comparison with other assay formats showed that this novel assay is substantially more sensitive in its ability to identify activators of NaV1.2 channel function relative to previous assay formats where the sodium channels have been forced to open via chemical means. Further, a number of the compounds were potent and efficacious activators with selectivity over the closely related NaV1.1 channel. Subsequent electrophysiological characterization showed that one hit, BRD4032, induces a shift in the voltage-dependence of NaV1.2 channel opening, causing it to open at lower membrane potentials. Further electrophysiology analysis of BRD4032 in mouse brain slices showed it elicits marked widening of the action potential waveform. Finally, in vivo EEG studies revealed that Scn2a+/- mice show significantly altered frequency bands, indicating that these alterations may be useful translational biomarkers.

Taken together, we have successfully implemented a robust screening strategy to identify NaV1.2 modulators based on a novel functional assay and are poised to advance compounds into our drug discovery pipeline that may eventually serve as leads towards treating ASD.

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paul karila
cso & director of pain research

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Presented by:

Jeff Cottrell, PhD
Vice President of Discovery at Delix Therapeutics
(former Director of Translational Research, Stanley Center for Psychiatric Research at the Broad Institute)

Jeff Cottrell is Vice President of Discovery at Delix Therapeutics, a startup company focused on the development of small-molecule compounds intended to help provide treatment against mental disorders such as depression and anxiety. Prior to joining Delix Therapeutics, Jeff was Director of Translational Research at the Stanley Center for Psychiatric Research at the Broad Institute. At Broad, he led a group with diverse expertise focused on translating discoveries of the genetics of psychiatric disease into research programs for the development of novel, mechanism-based treatments for these disorders.

Jeff came to the Broad Institute in 2015 after 11 years at Galenea, a biotechnology company focused on therapeutics for CNS disorders. At Galenea, he pioneered the development of high-throughput screening assays of synaptic transmission and their implementation for multiple drug discovery programs for neurodegenerative and psychiatric diseases. He has 20 years of experience in studying synapses and their dysfunction in disease and has demonstrated unique creativity throughout his career in translating these findings into novel approaches for therapeutic development. He holds a PhD in neuroscience from MIT and an A.B. in psychology from Harvard University.

Paul Karila, PhD
CSO & Director of Chronic Pain research at Cellectricon

Paul is a seasoned pre-clinical Drug Discovery expert with special interest in mechanistic models, phenotypic screening, and translational sciences. He joined Cellectricon in 2012 as head of Discovery Services. At Cellectricon, Paul and the team explore novel in vitro concepts for neurodegenerative diseases and chronic pain, which are developed into robust, high precision assays that can be accessed for screening, lead optimization and target discovery.

Paul previously worked at AstraZeneca (AZ) where he held leadership positions at the Departments of Molecular Pharmacology and Neuroscience. At AZ, he led teams responsible for target identification/target validation, ion channel and GPCR profiling, mainly in the chronic pain disease area. Prior to joining AZ, Paul was a Postdoctoral Fellow at School of Medicine, University of Pittsburgh, USA, studying neurobiology using electrophysiological methods, and a Graduate student in animal physiology at University of Gothenburg, Sweden.