Abstract
Background: Nociception is maintained by genome-wide regulation of transcription in the dorsal root ganglia—spinal cord network. Hence, transcription factors constitute a promising class of targets for breakthrough pharmacological interventions to treat chronic pain. DNA decoys are oligonucleotides and specific inhibitors of transcription factor activities. A methodological series of in vivo–in vitro screening cycles was performed with decoy/transcription factor couples to identify targets capable of producing a robust and long-lasting inhibition of established chronic pain. Decoys were injected intrathecally and their efficacy was tested in the spared nerve injury and chronic constriction injury models of chronic pain in rats using repetitive von Frey testing.
Results: Results demonstrated that a one-time administration of decoys binding to the Kruppel-like transcription factors (KLFs) 6, 9, and 15 produces a significant and weeks–month long reduction in mechanical hypersensitivity compared to controls. In the spared nerve injury model, decoy efficacy was correlated to its capacity to bind KLF15 and KLF9 at a specific ratio, while in the chronic constriction injury model, efficacy was correlated to the combined binding capacity to KLF6 and KLF9. AYX2, an 18-bp DNA decoy binding KLF6, KLF9, and KLF15, was optimized for clinical development, and it demonstrated significant efficacy in these models.
Conclusions: These data highlight KLF6, KLF9, and KLF15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain.
Document Type
Article
Publication Date
9-4-2017
Digital Object Identifier (DOI)
https://doi.org/10.1177/1744806917727917
Funding Information
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Adynxx, Inc.
Repository Citation
Mamet, Julien; Klukinov, Michael; Harris, Scott; Manning, Donald C.; Xie, Simon; Pascual, Conrado; Taylor, Bradley K.; Donahue, Renee R.; and Yeomans, David C., "Intrathecal Administration of AYX2 DNA Decoy Produces a Long-Term Pain Treatment in Rat Models of Chronic Pain by Inhibiting the KLF6, KLF9, and KLF15 Transcription Factors" (2017). Physiology Faculty Publications. 104.
https://uknowledge.uky.edu/physiology_facpub/104
Included in
Analytical, Diagnostic and Therapeutic Techniques and Equipment Commons, Pharmacology Commons, Pharmacy and Pharmaceutical Sciences Commons, Physiology Commons
Notes/Citation Information
Published in Molecular Pain, v. 13, p. 1-17.
© The Author(s) 2017
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).