PMID- 28814144
OWN - NLM
STAT- MEDLINE
DCOM- 20180904
LR  - 20190116
IS  - 1744-8069 (Electronic)
IS  - 1744-8069 (Linking)
VI  - 13
DP  - 2017 Jan-Dec
TI  - 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.
PG  - 1744806917727917
LID - 10.1177/1744806917727917 [doi]
LID - 1744806917727917
AB  - 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.
FAU - Mamet, Julien
AU  - Mamet J
FAU - Klukinov, Michael
AU  - Klukinov M
AD  - Stanford University CA.
FAU - Harris, Scott
AU  - Harris S
AD  - Adynxx, Inc., CA.
FAU - Manning, Donald C
AU  - Manning DC
AD  - Adynxx, Inc., CA.
FAU - Xie, Simon
AU  - Xie S
AD  - AfaSci Inc., CA.
FAU - Pascual, Conrado
AU  - Pascual C
AD  - AfaSci Inc., CA.
FAU - Taylor, Bradley K
AU  - Taylor BK
AD  - University of Kentucky, KY.
FAU - Donahue, Renee R
AU  - Donahue RR
AD  - University of Kentucky, KY.
FAU - Yeomans, David C
AU  - Yeomans DC
AD  - Stanford University CA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pain
JT  - Molecular pain
JID - 101242662
RN  - 0 (Klf15 protein, rat)
RN  - 0 (Klf6 protein, rat)
RN  - 0 (Kruppel-Like Factor 6)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Oligonucleotides)
RN  - 148686-29-7 (Klf9 protein, rat)
SB  - IM
MH  - Animals
MH  - Chronic Pain/*drug therapy/metabolism
MH  - Disease Models, Animal
MH  - Ganglia, Spinal/drug effects/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Kruppel-Like Factor 6/*drug effects
MH  - Kruppel-Like Transcription Factors/*drug effects
MH  - Male
MH  - Oligonucleotides/metabolism
MH  - Rats, Sprague-Dawley
MH  - Spinal Cord/drug effects/metabolism
PMC - PMC5582654
EDAT- 2017/08/18 06:00
MHDA- 2018/09/05 06:00
PMCR- 2017/08/17
CRDT- 2017/08/18 06:00
PHST- 2017/08/18 06:00 [entrez]
PHST- 2017/08/18 06:00 [pubmed]
PHST- 2018/09/05 06:00 [medline]
PHST- 2017/08/17 00:00 [pmc-release]
AID - 10.1177_1744806917727917 [pii]
AID - 10.1177/1744806917727917 [doi]
PST - ppublish
SO  - Mol Pain. 2017 Jan-Dec;13:1744806917727917. doi: 10.1177/1744806917727917.