Chronic pain limits activity and current treatments often contribute to further reduced function, limiting their chronic usage and creating a large unmet medical need. AYX2 is a drug candidate developed specifically to interrupt the maintenance and allow the resolution of chronic pain following a single or limited number of intrathecal administrations. Chronic pain is maintained through well-orchestrated waves of gene regulation across a wide range of gene categories within the dorsal root ganglia – spinal cord network. Transcription factors control gene expression and constitute a promising class of targets for transformative pharmacological interventions. Transcription factor decoys are powerful inhibitors of transcription factor activity. A series of decoys were designed against 35 complementary transcription factors or family of transcription factors to identify targets capable of producing a large and sustained resolution of chronic pain. These decoys were subjected to an in vivo - in vitro based attrition process and revealed that a one-time inhibition of the triumvirate of Kruppel-like transcription factors (KLF) 6, 9 and 15 produced a large reduction of mechanical hypersensitivity that was maintained until it resolved in control animals. The effect was observed in the spared nerve injury, chronic constriction injury and tibio-tarsal mono-arthritis models of chronic pain. Across pain states, the efficacy of a decoy relied either on its KLF15/KLF9 binding ratio or on the combined binding capacity to KLF6 and KLF9. AYX2 is an 18-bp long decoy that combines these complementary KLF6, 9 and 15 binding features and is optimized for clinical development. This work identifies KLF6, 9 and 15 as essential transcription factors for the maintenance of chronic pain. It further illustrates the potential clinical therapeutic benefits of AYX2 for producing a robust and long-term resolution of chronic pain states from multiple etiologies. This work is supported by Adynxx, Inc. Chronic pain limits activity and current treatments often contribute to further reduced function, limiting their chronic usage and creating a large unmet medical need. AYX2 is a drug candidate developed specifically to interrupt the maintenance and allow the resolution of chronic pain following a single or limited number of intrathecal administrations. Chronic pain is maintained through well-orchestrated waves of gene regulation across a wide range of gene categories within the dorsal root ganglia – spinal cord network. Transcription factors control gene expression and constitute a promising class of targets for transformative pharmacological interventions. Transcription factor decoys are powerful inhibitors of transcription factor activity. A series of decoys were designed against 35 complementary transcription factors or family of transcription factors to identify targets capable of producing a large and sustained resolution of chronic pain. These decoys were subjected to an in vivo - in vitro based attrition process and revealed that a one-time inhibition of the triumvirate of Kruppel-like transcription factors (KLF) 6, 9 and 15 produced a large reduction of mechanical hypersensitivity that was maintained until it resolved in control animals. The effect was observed in the spared nerve injury, chronic constriction injury and tibio-tarsal mono-arthritis models of chronic pain. Across pain states, the efficacy of a decoy relied either on its KLF15/KLF9 binding ratio or on the combined binding capacity to KLF6 and KLF9. AYX2 is an 18-bp long decoy that combines these complementary KLF6, 9 and 15 binding features and is optimized for clinical development. This work identifies KLF6, 9 and 15 as essential transcription factors for the maintenance of chronic pain. It further illustrates the potential clinical therapeutic benefits of AYX2 for producing a robust and long-term resolution of chronic pain states from multiple etiologies. This work is supported by Adynxx, Inc.