Pharmacology, pharmacokinetics, and metabolism of the DNA-decoy AYX1 for the prevention of acute and chronic post-surgical pain

Abstract

BackgroundAYX1 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.ResultsThe 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.DiscussionAYX1 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.ConclusionsThese 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.

Simultaneous targeted inhibition of Sox2‐Oct4 transcription factors using decoy oligodeoxynucleotides to repress stemness properties in mouse embryonic stem cells

“…This approach, in its simple or complex form, has been tested with various TFs involved in cancers or immunological disorders, including E2F (Ahn et al, 2003), NF-kB (Takahashi et al, 2009), CRE (Liu et al, 2004), AP1 (Cho et al, 2006), SP1 (Park et al, 2009), andSTAT1 (H€ olschermann et al, 2006), and also with those involved in viral infections, for example, HIV-1 (Li et al, 2005), HCV (Zhang et al, 2005), STAT3 (Zhang et al, 2010), Myc/Oct4/Sox2 (Wang et al, 2013), Myc (El-Andaloussi et al, 2005, Johari et al, 2017, Nanog/Oct4 (Rad et al, 2015), SOX18 (Klaus et al, 2016), and AYX1 (Mamet et al, 2017).…”

Involvement of transient receptor potential vanilloid 2 in intra‐oral incisional pain

“…To date, there are few reports regarding pathological pain hypersensitivity relevant to oral mucosal injury, although previous studies have shown that post-traumatic pain hypersensitivity was induced in a traumatic injury model (Kumar, Sarumathi, Veerabahu, & Raman, 2013;Liu et al, 2017;Mamet et al, 2017). Clinically, it has long been known that the oral mucosa is unique in its mechanical and thermal sensitivity compared with that of the skin, suggesting that the mechanical and thermal sensory mechanisms in the oral mucosa are different from those of the body's surface (Green & Gelhard, 1987;Komiyama & De Laat, 2005).…”

Is there an unmet pharmacological need in chronic lower back pain?

“…Transcription factor decoys function as inhibitors of transcription factor activity. Such decoys were tested and led to the inhibition of Kruppel-like transcription factors (KLF), resulting in a reduction of mechanical hypersensitivity in animal models [12]. The company's website communicates that AYX2 is specifically designed to target multiple transcription factors that sustain chronic pain due to inflammatory and/or neuropathic insult.…”