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FXYD2 antisense oligonucleotide provides an efficient approach for long-lasting relief of chronic peripheral pain
- Source :
- JCI Insight, Vol 8, Iss 9 (2023)
- Publication Year :
- 2023
- Publisher :
- American Society for Clinical investigation, 2023.
-
Abstract
- 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.
- Subjects :
- Neuroscience
Medicine
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 8
- Issue :
- 9
- Database :
- Directory of Open Access Journals
- Journal :
- JCI Insight
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.12668065e27441908f0e18635bd35a29
- Document Type :
- article
- Full Text :
- https://doi.org/10.1172/jci.insight.161246