Scientific programme

eP65  E-POSTER - 6-9 SEPTEMBER 2017
PAIN TREATMENT (CONSERVATIVE): NOVEL THERAPEUTIC AGENTS

06-Sep-2017 11:30 20:00
 
 
Abstract:
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

Aims: Nociception is maintained by long-term gene regulations in the dorsal root ganglia and spinal cord. Hence transcription factors, which directly control gene expression, constitute a promising class of targets for breakthrough pharmacological interventions. DNA-decoys are oligonucleotides that inhibit transcription factor activities by mimicking their binding sites on the genome. A methodological series of in vivo-in vitro screenings was performed with 35 decoy/transcription factors couples to identify AYX2, a novel decoy producing a long-lasting resolution of chronic pain following a single intrathecal injection.

Methods: Decoys efficacy tested was in the spared nerve injury (SNI) and chronic constriction injury (CCI) models of chronic pain in rats using repetitive von Frey testing. Decoys binding to transcription factors was measured with ELISA.

Results: A one-time, decoy-inhibition of Kruppel-like transcription factors (KLF) 6, 9 and 15 reduced mechanical hypersensitivity for weeks until it was resolving in vehicle-treated animals. The effect was observed in both SNI and CCI models. In the SNI model, efficacy of a decoy was driven by its KLF15/KLF9 binding ratio. In the CCI model, it was driven by its total binding capacity to KLF6 and KLF9, regardless of the ratio. AYX2 is an 18-bp long decoy that combines these complementary KLF6, 9 and 15 binding features and is optimized for clinical development.

Conclusions: These data highlight KLF6, 9 and 15 as transcription factors required for the maintenance of chronic pain and illustrate the potential therapeutic benefits of AYX2 for the treatment of chronic pain.

 Funding Adynxx Inc.           

 
Co-authors
J. Mamet 1, M. Klukinov 2, S. Harris 1, D. Manning 1, S. Xie 3, C. Pascual 3, B. Taylor 4, R. Donahue 4, D. Yeomans 2
1Adynxx- Inc, N/A, San Francisco, USA
2Stanford University, Anesthesia, Stanford, USA
3AfaSci- Inc, N/A, Redwood City, USA
4University of Kentucky, Physiology, Lexington, USA