143: Targeting FXYD2 to Prevent and Reverse Chemotherapy-Induced Neuropathic Pain

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic cancer related pain, , , , , , , Drug development, ,

Background and Aims: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and severe adverse effect of chemotherapy, characterized by persistent mechanical and cold pain, for which effective treatments are lacking. We previously identified the Na,K-ATPase modulator Fxyd2, expressed in nociceptive sensory neurons, as a critical contributor to chronic neuropathic pain [1], a role also described in inflammatory pain [2]. Targeting FXYD2 using lipid-modified antisense oligonucleotides (FXYD2-LASO-Gapmer) has shown analgesic efficacy in preclinical models, correlated with altered excitability of nociceptors [3]. This study aimed to evaluate the preventive and therapeutic potential of FXYD2-LASO-Gapmer in a rat model of OIPN.

Methods: Peripheral neuropathy was induced in rats by repeated oxaliplatin administration. Two treatment strategies were used: a curative protocol, in which FXYD2-LASO-Gapmer or a Control-LASO-Gapmer was administered after neuropathy onset, and a preventive protocol, in which treatments were given prior to oxaliplatin exposure. Mechanical and thermal hypersensitivities were assessed longitudinally using validated behavioral tests. Evoked mechanical hypersensitivity was evaluated with the von Frey and Randall–Selitto tests, and evoked thermal hypersensitivity with the tail immersion test. Non-evoked thermal behaviors were assessed using the thermal place preference test. Together, these tests characterized the development and persistence of nociceptive behaviors.

Results: Oxaliplatin-treated rats developed pronounced mechanical and cold hypersensitivity. In the curative protocol, hypersensitivity persisted in control-treated animals but was significantly reduced and did not persist in rats receiving FXYD2-LASO-Gapmer. In the preventive protocol, FXYD2-LASO-Gapmer administration protected animals from developing mechanical and cold hypersensitivity following oxaliplatin treatment, whereas control-treated rats exhibited robust pain behaviors.

Conclusions: These results indicate that inhibition of FXYD2 expression using a lipid-modified antisense oligonucleotide effectively prevents and alleviates oxaliplatin-induced neuropathic pain in rats. With the growing development of antisense oligonucleotide–based therapeutic strategies in the pharmaceutical industry, the FXYD2-LASO-Gapmer emerges as a particularly promising preventive and therapeutic approach for managing painful chemotherapy-induced peripheral neuropathy.

References: [1] S. Ventéo et al., ‘Fxyd2 regulates Aδ- and C-fiber mechanosensitivity and is required for the maintenance of neuropathic pain’, Sci. Rep., vol. 6, no. 1, p. 36407, Nov. 2016, doi: 10.1038/srep36407.
[2] F. Wang et al., ‘FXYD2, a γ subunit of Na+,K+-ATPase, maintains persistent mechanical allodynia induced by inflammation’, Cell Res., vol. 25, no. 3, pp. 318–334, Mar. 2015, doi: 10.1038/cr.2015.12.
[3] A. Derre et al., ‘FXYD2 antisense oligonucleotide provides an efficient approach for long-lasting relief of chronic peripheral pain’, JCI Insight, vol. 8, no. 9, p. e161246, doi: 10.1172/jci.insight.161246.

Presenting Author: VENTEO Stéphanie
Submitting Author: Stephanie Venteo

Senior Author: VENTEO Stéphanie

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• SOLER Noélian: Assistant engineer - Inserm
• RIGAUD Aurelie: PhD student - Inserm
• BARTHELEMY Philippe: Researcher - Inserm
• ANGO Frabrice: Researcher - Inserm
• CARROLL Patrick: Researcher - Inserm
• PATTYN Alexandre: Researcher - Inserm
• MASKINI Dounia: PhD student - Inserm