Development of an alpha-conotoxin RgIA analog as a novel, non-opioid therapeutic for chronic neuropathic pain

PROJECT SUMMARY The objective of this SBIR Phase I application is to select an optimized lead analog ofconotoxin RgIA to develop as a uniquenon opioid therapeutic for chronic neuropathic painRgIAa peptide derived from the predatory marine cone snail Conus regiusis an inhibitor of thenicotinic acetylcholine receptornAChRa novel genetically validated pain targetOur current lead candidateKCPpotently and selectively inhibits both the rat and human target and displays analgesic efficacy in animal models of neuropathic painMoreoverRgIA and its analogs have anti inflammatory and neuroprotective effectsthereby providing a neuropathic pain management strategy that includes both symptom reduction and disease modificationKCPprovides a novelnon opioid mechanism of action that is distinct from all other commercially available products for the treatment of painHerewe propose to further optimize KCPto increase its stability and bioavailability and enhance its therapeutic potentialThe Specific Aims of this proposal are tooptimize KCPto increase its bioavailability while maintaining its target specificityandevaluate the efficacy and safety of the optimized KCPin a nerve injury model of neuropathic painPeptide modifications to increase stability will include substitution of disulfide bridges with a stable backbone cross linker and peptide lipidation and pegylationAnalgesic potency of optimized KCPwill be evaluated through dose response and comparative efficacy studies using the rat chronic constriction injury model of sciatic nerve injury and neuropathic painThis work will provide an optimized preclinical development candidate for investigational new drugINDenabling studies during SBIR Phase IIThe significance of the program is its emphasis on an analgesic product with reduced susceptibility to analgesic tolerance and drug abuse and anticipated significant impact on reducing the global burden of neuropathic painInnovation relates to the focus on a stableconotoxin RgIA analog with high potency and specificity for a new molecular target and diseasemodifying neuroprotective activityThe key deliverable of this project is an optimizedlong actingnon opioid analgesic drug candidate with good safetytolerabilityand efficacy in animal models of neuropathic pain PROJECT NARRATIVE This project addresses the need to phase out opioids as the major pain relieving drugs for chronic painWe are developing a new type of analgesic drugderived from a peptide found in the venom of a predatory marine cone snailfor use in treating chronic pain that results from nerve injury due to traumadiabetesinfectionsor chemotherapyOur lead candidateKCPis unique in providing both non addictive pain relief as well as anti inflammatory and neuroprotective effects that may have disease modifying actions on chronic pain