Quiver Bioscience

We recently published an innovative in vitro system for modeling chronic pain associated with osteoarthritis (OA), a condition that affects over 30 million patients in the US. Our Pain Therapeutics team, led by Hongkang Zhang and Owen McManus are leveraging the power of this model, which uses Quiver’s proprietary high-throughput all-optical electrophysiology platform, to develop novel non-opioid therapeutics for the treatment of pain disorders. The work, published in Pain – The Journal of the International Association for the Study of Pain, defines a “pain-in-a-dish” model that more accurately represents the relevant physiological environment for evaluating aspects of sensory neuron function associated with OA chronic pain in a scalable format needed to support therapeutic discovery. Furthermore, the data presented here supports the use of this model for effective phenotypic screening for novel pain therapeutics discovery and as a means to directly evaluate pharmacological effects of candidate molecules in a key tissue for pain signaling. “Our platform enables recordings from approximately 20,000 sensory neurons per multi-well plate with single-cell and single-action-potential resolution and it provides rich information content that is used to define OA pain phenotypes and mechanisms as well as characterize candidate therapeutic compounds” states Hongkang Zhang, a lead author on the manuscript.   📄 | Read the full manuscript here: https://lnkd.in/dqK_BgC8   Summary: To establish the “pain-in-a-dish” model, the team first defined OA-SPARC (OA-derived Sensitizing Pain Reagent Composition), a mixture of inflammatory compounds known to be elevated in the joints of OA patients and demonstrated to elicit a pain response following injection into rat hind paw. OA-SPARC was applied to cultured rat dorsal root ganglion neurons and optogenetic recordings were obtained from individual neurons to interrogate a battery of electrophysiological features at high-throughput scale. Multidimensional analysis revealed a unique OA-SPARC-induced neuronal phenotype, characterized by increased excitability, which could be rescued by treatment with known analgesics. Finally, the curated OA-SPARC phenotype was used in a phenotypic screen of a library of roughly 3,000 small molecules including approved drugs and compounds targeting known neuronal signaling pathways. Confirmed hits shown to specifically reverse the OA-SPARC phenotype implicated select cell signaling pathways and molecular targets, including the MAPK pathway component MEK, in OA pain pathophysiology and suggest potential targets for therapeutic intervention. Quiver is continuing to develop and apply the OA-SPARC assay to evaluate pain phenotypes using human induced pluripotent stem cell-derived sensory neurons and enable discovery of improved pain therapeutics. #pain #neuroscience #drugdiscovery