Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury

Julien Mamet; Michael Klukinov; Tony L. Yaksh; Shelle A. Malkmus; Samantha Williams; Scott Harris; Donald C. Manning; Bradley K. Taylor; Renee R. Donahue; Frank Porreca; Jennifer Y. Xie; Janice Oyarzo; Timothy J. Brennan; Alberto Subieta; William K. Schmidt; David C. Yeomans

doi:10.1016/j.pain.2013.10.015

Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury

Julien Mamet, Michael Klukinov, Tony L. Yaksh, Shelle A. Malkmus, Samantha Williams, Scott Harris, Donald C. Manning, Bradley K. Taylor, Renee R. Donahue, Frank Porreca, Jennifer Y. Xie, Janice Oyarzo, Timothy J. Brennan, Alberto Subieta, William K. Schmidt, David C. Yeomans

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.

Original language	English (US)
Pages (from-to)	322-333
Number of pages	12
Journal	Pain
Volume	155
Issue number	2
DOIs	https://doi.org/10.1016/j.pain.2013.10.015
State	Published - Feb 2014

Keywords

AYX1
Acute
Chronic
Oligonucleotide
Post-surgical pain
Prevention

ASJC Scopus subject areas

Neurology
Clinical Neurology
Anesthesiology and Pain Medicine

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10.1016/j.pain.2013.10.015

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Mamet, J., Klukinov, M., Yaksh, T. L., Malkmus, S. A., Williams, S., Harris, S., Manning, D. C., Taylor, B. K., Donahue, R. R., Porreca, F., Xie, J. Y., Oyarzo, J., Brennan, T. J., Subieta, A., Schmidt, W. K., & Yeomans, D. C. (2014). Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury. Pain, 155(2), 322-333. https://doi.org/10.1016/j.pain.2013.10.015

Mamet, J, Klukinov, M, Yaksh, TL, Malkmus, SA, Williams, S, Harris, S, Manning, DC, Taylor, BK, Donahue, RR, Porreca, F, Xie, JY, Oyarzo, J, Brennan, TJ, Subieta, A, Schmidt, WK & Yeomans, DC 2014, 'Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury', Pain, vol. 155, no. 2, pp. 322-333. https://doi.org/10.1016/j.pain.2013.10.015

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title = "Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury",

abstract = "The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.",

keywords = "AYX1, Acute, Chronic, Oligonucleotide, Post-surgical pain, Prevention",

author = "Julien Mamet and Michael Klukinov and Yaksh, {Tony L.} and Malkmus, {Shelle A.} and Samantha Williams and Scott Harris and Manning, {Donald C.} and Taylor, {Bradley K.} and Donahue, {Renee R.} and Frank Porreca and Xie, {Jennifer Y.} and Janice Oyarzo and Brennan, {Timothy J.} and Alberto Subieta and Schmidt, {William K.} and Yeomans, {David C.}",

note = "Funding Information: The authors thank Dr. Brenda Bart-Knauer (U.S. Army Medical Research & Material Command Telemedicine & Advanced Technologies Research Center (TATRC) for her great support and guidance in the accomplishment of this work . This study was funded by Adynxx, Inc. and supported by a US Army/TATRC Grant (award no. W81XWH-10-2-0012 ).",

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doi = "10.1016/j.pain.2013.10.015",

language = "English (US)",

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AU - Mamet, Julien

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AU - Malkmus, Shelle A.

AU - Williams, Samantha

AU - Harris, Scott

AU - Manning, Donald C.

AU - Taylor, Bradley K.

AU - Donahue, Renee R.

AU - Porreca, Frank

AU - Xie, Jennifer Y.

AU - Oyarzo, Janice

AU - Brennan, Timothy J.

AU - Subieta, Alberto

AU - Schmidt, William K.

AU - Yeomans, David C.

N1 - Funding Information: The authors thank Dr. Brenda Bart-Knauer (U.S. Army Medical Research & Material Command Telemedicine & Advanced Technologies Research Center (TATRC) for her great support and guidance in the accomplishment of this work . This study was funded by Adynxx, Inc. and supported by a US Army/TATRC Grant (award no. W81XWH-10-2-0012 ).

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N2 - The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain.

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Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury

Abstract

Keywords

ASJC Scopus subject areas

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