An all-optical electrophysiology platform for the discovery of pain therapeutics

Project Summary Chronic pain affects overmillion adults in the United States and is challenging to treatCurrent treatments include opioids and non steroidal inflammatory agentsHoweverefficacy of these drugs in chronic treatment is restricted by dose limiting toxicitiesand prolonged opioid use can lead to dependencyDespite the clearunmet medical need and significant research activityfew drugs targeting pain based on novelnon opioid mechanisms have appeared in the past decadeQ state has created a novel all optical platformOptopatchusing engineered optogenetic proteins and custom microscopes to simultaneously stimulate and record electrical activity from a variety of cell types with high sensitivity and temporal resolutionWe focus our efforts on a genetically validated pain targetSCN ANava voltage gated sodium channel that is required for pain signal transmission in sensory neuronsWe will apply Optopatch technology in two formatsAn HTS screen of the Q State chemical library using a heterologously expressed Navchannel assay that replicates physiological spiking activityCounterscreens against other Navx channels will be performed in the same assay format to determine compound selectivityIdentified inhibitors will be evaluated in medium throughput screens that measure excitability in rodent sensory and human iPS sensory neurons that have been sensitized using inflammatory mediatorsThis integrated set of assays is designed to identify Navinhibitors acting by diverse working mechanisms and prioritize compounds for further optimization using scalable in vitro models of sensory neuron functionThis platform will be employed as an efficient means to select compounds for optimization using medicinal chemistry and pharmacokineticdrug metabolism and in vivo efficacy data Despite the clearunmet medical need and significant research activityfew drugs targeting pain based on novelnon opioid mechanisms have appeared in the past decadeQ state has created an integrated platform using engineered optogenetic proteins and custom microscopes to simultaneously stimulate and record electrical activity from a variety of cell types with high sensitivity and temporal resolutionWe focus our efforts on a genetically validated pain targetSCN ANava voltage gated sodium channel that is required for pain signal transmission in sensory neuronsQ State will identify and optimize Navinhibitors that also reduce excitability in rodent and human sensory neurons that have been sensitized by agents that promote chronic pain