DOI: 10.5061/dryad.dh250
title: Data from: Formulation and toxicology evaluation of the intrathecal AYX1 DNA-decoy in Sprague Dawley rats

description: 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 perioperative dose. AYX1
 mimics the DNA sequence normally bound by EGR1 on chromosomes, a
 transcription factor transiently induced in the dorsal root ganglia—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 nonGLP study was
 conducted in the spared nerve injury model of chronic neuropathic pain in
 which EGR1 is induced in the dorsal root ganglia 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 was judged to be the maximum feasible
 dose.
description: Mamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental protocol
 informationSupplemental protocol
 informationMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 1Stability of AYX1:
 calcium formulation with sodium phosphate or Tris buffers at 2
 weeksMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 2Stability of the AYX1:
 calcium formulation with Tris buffer at 3 monthsMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 3Clinical laboratory
 assessments of female rats at Day 3 and 30 in the ADY-TX2
 studyMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 4ADY-TX2 study,
 Functional observation battery results, pre-dose and 4h post-dosing of Day
 3 animalsMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 5Histopathology analysis
 of lumbar spinal cord of female rats in the ADY-TX2
 studyMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 6Summary of Total AYX1
 (full length + metabolites) toxicokinetics in the CSF and plasma of male
 and female rats in the ADY-TX2 studyMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Tables
 7abcIrwin Test, SNITX1
 studyMamet et al, 2017 -
 Toxicological Sciences - 05 28 17 -Supplemental Table 8Clinical laboratory
 assessments at study Day 14 in the ADY-SNITX1 studyMamet et al, 2017 -
 Toxicological Sciences - 05 25 17 -Supplemental Table 9Histopathology
 evaluation at necropsy 14 days following dosing/SNI surgery, SNITX1
 study