Data from: Formulation and toxicology evaluation of the intrathecal AYX1 DNA-decoy in Sprague Dawley rats

The longevity of pain after surgery is debilitating and limits the recovery of patients. AYX1 is a double-stranded, unprotected, 23 base-pair oligonucleotide designed to reduce acute post-surgical pain and prevent its chronification with a single intrathecal peri-operative dose. AYX1 mimics the DNA sequence normally bound by EGR1 on chromosomes, a transcription factor transiently induced in the dorsal root ganglia (DRG) - spinal cord network following a noxious input. AYX1 binds to EGR1 and prevents it from launching waves of gene regulation that are necessary to maintain pain over time. A formulation suitable for an intrathecal injection of AYX1 was developed, including a specific ratio of AYX1 and calcium so the ionic homeostasis of the cerebrospinal fluid is maintained and no impact on neuromuscular control is produced upon injection. A GLP toxicology study in naïve Sprague Dawley rats was conducted using 3 dose levels up to the maximum feasible dose. Clinical observations, neurobehavioral observations, clinical pathology and histopathology of the nervous system and peripheral tissues were conducted. An additional non-GLP study was conducted in the spared nerve injury model of chronic neuropathic pain in which EGR1 is induced in the DRG and spinal cord. Similar testing was performed, including a modified Irwin test to assess a potential impact of AYX1 on autonomic nervous system responses, locomotion, activity, arousal, sensorimotor and neuromuscular function. No AYX1-related adverse events were observed in any of the studies and the no-observed-adverse-effect-level (NOAEL) was judged to be the maximum feasible dose.