Project Summary/Abstract Current pharmacological and surgical treatments frequently fail to produce effective and/or durable neuropathic pain relief and are associated with severe side- or off-target effects. CODA Biotherapeutics is developing a powerful, targeted approach to treating chronic neuropathic pain that overcomes many conventional limitations. Our chemogenetic strategy is unique in that it targets the hyperactivity of primary sensory neurons (both nociceptive and mechanosensitive), a common pathophysiology of neuropathic pain. We have engineered inhibitory ligand-gated ion channel receptors that lack sensitivity to the endogenous ligand but retain or have enhanced sensitivity to a clinically safe agonists acquired by CODA (phase 1&2 clinical data packages available). Localized delivery of the receptor to primary sensory neurons in dorsal root or trigeminal ganglion is readily achieved using AAV gene therapy combined with standard-of-care procedures. Systemic delivery of the agonist with oral administration will activate the CODA receptor in a dose-dependent manner. CODA has completed high-throughput screening of thousands of potential receptor-agonist combinations and has identified several leads. One current lead, CODA806, when compared to the WT receptor, possesses very high sensitivity to one of the agonists (Compound-2) and very low sensitivity to its endogenous ligand. In vitro studies in rat DRG neurons demonstrated that the CODA806 receptor is expressed on the neuronal cell surface, passes chloride current only with application of Compound-2, and blocks current induced action potentials. These findings have been extended to show silencing of spontaneous activity in rat DRG and hippocampal cultures. The work described herein provides a foundation for optimizing the receptor/small-molecule agonist combination and will demonstrate proof-of-concept in vivo. The first objective is to optimize expression level and durability of CODA806 in DRG neurons in vivo. We provide AAV pilot data with a GFP reporter molecule showing >50% transduction of DRG neurons with direct injection. Next, we will conduct proof-of-concept studies of the CODA806/Compound-2 pair in a rodent model of neuropathic pain (spared-nerve injury). We reduced the risk of failure and minimized required regulatory safety studies through two strategies (1) CODA has acquired the data packages for selected agonists and (2) we have selected well established, clinically utilized AAV capsids and expression cassettes. Therefore, we expect the preclinical\clinical studies will focus on receptor expression and safety, followed by the safety and efficacy of the receptor\agonist expression (possibly achieved in one clinical trial). In addition to developing a novel therapy for neuropathic pain, the research described here will further our understanding of how hyperactivity of sensory neurons (eg, subtypes) plays a role in neuropathic pain and the potential for novel treatments that m...