title: Pharmacology, pharmacokinetics, and metabolism of the DNA-decoy AYX1 for the prevention of acute and chronic post-surgical pain.
abstract: Background AYX1 is an unmodified DNA-decoy designed to reduce acute post-surgical pain and its chronification with a single intrathecal dose at the time of surgery. AYX1 inhibits the transcription factor early growth response protein 1, which is transiently induced at the time of injury and triggers gene regulation in the dorsal root ganglia and spinal cord that leads to long-term sensitization and pain. This work characterizes the AYX1 dose-response profile in rats and the link to AYX1 pharmacokinetics and metabolism in the cerebrospinal fluid, dorsal root ganglia, and spinal cord. Results The effects of ascending dose-levels of AYX1 on mechanical hypersensitivity were measured in the spared nerve injury model of chronic pain and in a plantar incision model of acute post-surgical pain. AYX1 dose-response profile shows that efficacy rapidly increases from a minimum effective dose of ∼ 0.5 mg to a peak maximum effective dose of ∼ 1 mg. With further dose escalation, the efficacy paradoxically appears to decrease by ∼ 30% and then returns to full efficacy at the maximum feasible dose of ∼ 4 mg. The reduction of efficacy is associated to doses triggering a near-saturation of AYX1 metabolism by nucleases in the cerebrospinal fluid and a paradoxical reduction of AYX1 exposure during the period of early growth response protein 1 induction. This effect is overcome at higher doses that compensate for the effect of metabolism. Discussion AYX1 is a competitive antagonist of early growth response protein 1, which is consistent with the overall increased efficacy observed as dose-levels initially escalate. Chemically, AYX1 is unprotected against degradation by nucleases. The sensitivity to nucleases is reflected in a paradoxical reduction of efficacy in the dose-response curve. Conclusions These findings point to the importance of the nuclease environment of the cerebrospinal fluid to the research and development of AYX1 and other intrathecal nucleotide-based therapeutics.
authors.affiliation: 1 Adynxx, Inc., CA, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Mamet
authors.affiliation: 1 Adynxx, Inc., CA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Harris
authors.affiliation: 2 Department of Anesthesia, Stanford University, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Klukinov
authors.affiliation: 2 Department of Anesthesia, Stanford University, CA, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Yeomans
authors.affiliation: 3 Department of Physiology, University of Kentucky, KY, USA.
authors.forename: Renee R
authors.initials: RR
authors.lastname: Donahue
authors.affiliation: 3 Department of Physiology, University of Kentucky, KY, USA.
authors.forename: Brad K
authors.initials: BK
authors.lastname: Taylor
authors.affiliation: 4 Department of Anesthesiology and Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Eddinger
authors.affiliation: 4 Department of Anesthesiology and Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Yaksh
authors.affiliation: 1 Adynxx, Inc., CA, USA.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Manning
mesh_terms: D059787:Acute Pain / Q000209:etiology / Q000517:prevention & control*; D000700:Analgesics / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D059350:Chronic Pain / Q000209:etiology / Q000517:prevention & control*; D004247:DNA / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement; D010149:Postoperative Pain / Q000150:complications / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects
chemical_list: D000700:Analgesics; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D009841:Oligonucleotides; D004247:DNA
keywords: Chronic pain; cerebrospinal fluid; early growth response protein 1; nucleases; oligonucleotide