A phenotypic screen for osteoarthritic pain therapeutics using all-optical electrophysiology.

Project SummaryA phenotypic screen for osteoarthritic pain therapeutics using alloptical electrophysiology Chronic pain affects overmillion adults in the United Statesmany of whom cannot find relief with current medicationsOf these patientsnearlyof them suffer from osteoarthritisCurrent treatments for chronic pain include opioids and non steroidal inflammatory agentsHoweverefficacy of these drugs in chronic treatment is restricted by the development of tolerance and dose limiting toxicitiesOpioids in particular are highly addictiveand dependency has caused a large societal burdenDespite the clearunmet medical need and significant research activityfew new classes of non opioid drugs targeting chronic pain have appeared in the past decadeQuell Therapeutics uses the Optopatch platform for making all optical electrophysiology measurements in neurons at a throughput sufficient for phenotypic screeningUsing engineered optogenetic proteinsblue and red light can be used to stimulate and record neuronal activityrespectivelyCustom microscopes enable electrophysiology recordings froms of individual neurons in parallel with high sensitivity and temporal resolutiona capability currently not available with any other platform screening technologyHerewe combine the Optopatch platform with an in vitro model of chronic painwhere dorsal root ganglionDRGsensory neurons are bathed in a mixture of inflammatory mediators found in the joints of osteoarthritis patientsThe neurons treated with the inflammatory mixture become hyperexcitablemimicking the anticipated cellular pain responseWe calculate the functional phenotype of arthritis painwhich captures the difference in action potential shape and firing rate in response to diverse stimuliWe will screen for small molecule compounds that reverse the pain phenotype while minimizing perturbation of neuronal behavior orthogonal to the pain phenotypethe in vitroside effectsWe will counter screen against neurons from the cerebral cortex and cardiomyocytes from the heart to prioritize compounds that act selectively in inflamed sensory neuronsThe highest ranking compounds will be chemically optimized and their pharmacokineticdrug metabolismand in vivo efficacy will be characterizedOur goal is to advance therapeutic discovery for painwhich may ultimately help relieve the US opioid crisis Project NarrativeA phenotypic screen for osteoarthritic pain therapeutics using alloptical electrophysiology Despite the clearunmet medical needthe last decade of active research has yielded few novelnon opioid drugs targeting arthritic and other forms of chronic painQuell Therapeutics has an integrated platform using engineered optogenetic proteins and custom microscopes to simultaneously stimulate and record electrical activity froms of neurons in parallel with high sensitivity and temporal resolutionHerewe make adisease in a dishmodel of chronic osteoarthritis pain by bathing sensory neurons in a cocktail of inflammatory signaling molecules found in arthritic jointsand screen for drugs that counteract the induced inflammation