FXYD2 antisense oligonucleotide provides an efficient approach for long-lasting relief of chronic peripheral pain

JCI Insight. 2023 May 8;8(9):e161246. doi: 10.1172/jci.insight.161246.


Chronic pain, whether of inflammatory or neuropathic origin, affects about 18% of the population of developed countries, and most current treatments are only moderately effective and/or cause serious side effects. Therefore, the development of novel therapeutic approaches still represents a major challenge. The Na,K-ATPase modulator FXYD2 is critically required for the maintenance of neuropathic pain in rodents. Here, we set up a therapeutic protocol based on the use of chemically modified antisense oligonucleotides (ASOs) to inhibit FXYD2 expression and treat chronic pain. We identified an ASO targeting a 20-nucleotide stretch in the FXYD2 mRNA that is evolutionarily conserved between rats and humans and is a potent inhibitor of FXYD2 expression. We used this sequence to synthesize lipid-modified forms of ASO (FXYD2-LASO) to facilitate their entry into dorsal root ganglia neurons. We established that intrathecal or intravenous injections of FXYD2-LASO in rat models of neuropathic or inflammatory pain led to a virtually complete alleviation of their pain symptoms, without causing obvious side effects. Remarkably, by using 2'-O-2-methoxyethyl chemical stabilization of the ASO (FXYD2-LASO-Gapmer), we could significantly prolong the therapeutic action of a single treatment up to 10 days. This study establishes FXYD2-LASO-Gapmer administration as a promising and efficient therapeutic strategy for long-lasting relief of chronic pain conditions in human patients.

Keywords: Neuroscience; Pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chronic Disease
  • Chronic Pain* / drug therapy
  • Chronic Pain* / genetics
  • Humans
  • Neuralgia* / drug therapy
  • Oligonucleotides
  • Oligonucleotides, Antisense / pharmacology
  • Rats
  • Sodium-Potassium-Exchanging ATPase / metabolism


  • Oligonucleotides, Antisense
  • Sodium-Potassium-Exchanging ATPase
  • Oligonucleotides
  • FXYD2 protein, human