Ultra-high-throughput plate reader for drug discovery using all-optical electrophysiology - Project Summary: Ultra-high-throughput plate reader for drug discovery using all-optical electrophysiology Neurological disorders remain a major unmet medical need in the United States and worldwide, accounting for more than 10% of the total years of healthy life lost in developed countries. Drug discovery for diseases of the nervous system has been challenging in comparison with other disease areas. A major barrier to progress in neuroscience drug discovery is the lack of translatable assays, models, and technologies that can be used to predict human efficacy with both the information content and throughput needed for rapid identification and optimization of therapeutic candidates. As such, there is a strong commercial need for scalable assay and instrument platforms that can be leveraged throughout the CNS-based drug screening and discovery pipeline. The Swarm microscope, developed through Phase I and Phase II efforts, leverages Q-State’s proprietary Optopatch technology, enabling the recording of both voltage and calcium activity under optical stimulation from 24-objectives simultaneously. Our instrument has the potential to transform high-throughput screening (HTS) by leveraging our advanced optogenetics tools in 96-, 384-, and 1536-well plate formats. The instrument was successfully used to screen Q-State’s 200,000 internal compound library against Nav1.7, a genetically validated target for pain, on our Spiking HEK cell assay demonstrating the utility of the Swarm for CNS-based therapeutic discovery. In this Phase IIB application, Q-State will leverage these technologies and expertise towards full commercialization by building the next generation Swarm 2.0 platform with significantly improved functionality, throughput, and stability. First, we will develop a camera-based Swarm 2.0 instrument with upgraded illumination, stimulation, and detection subassemblies and pair these capabilities with new analysis tools. Next, we will develop two differentiating Swarm 2.0 compatible optogenetic classes of assays: 1) target-based HEK cell assays for voltage-gated Na channels, representing a major class of drug targets for CNS disorders, and 2) intact, native cell assays in neurons, enabling critical bridging secondary assays for therapeutic discovery. After the instrument is constructed and validated, we will optimize Nav1.8, a drug target for pain indications currently pursued by the pharmaceutical industry, and secondary multiplexed spiking HEK assays for HTS compatibility on the platform. Finally, we will perform a screening campaign using an in-house library of approximately 200,000 small molecules for inhibitors of Nav1.8 followed by the hit confirmation and selectivity counter-screens. At the conclusion of this Phase IIB work, the Swarm 2.0 platform will be fully validated for commercialization, generating chemical hits that can be optimized for pain therapeutics and more broadly by enabling execution of HTS compound screens with the potential for expansion into new assay types. Success in Phase IIB has the potential for significant impact both in neuroscience research and in enabling our novel, proprietary platform for drug discovery for CNS-based disorders such as severe epilepsy and pain, areas of significant unmet medical need.
