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Modulation of Pro-Inflammatory IL-6 Trans-Signaling Axis by Splice Switching Oligonucleotides as a Therapeutic
Dhanu Gupta1,2, Sara Orehek2, Janne Turunen2
1Department of Paediatrics, University of Oxford, Oxford OX3 7TY, UK.
Cells
|September 28, 2023
Summary
A novel gene therapy approach specifically targets Interleukin-6 (IL-6) trans-signaling by modulating Glycoprotein 130 (GP130) splicing. This method reduces inflammation in mouse models, offering potential for chronic inflammatory diseases.
Area of Science:
- Immunology and Molecular Biology
- Gene Therapy and Drug Development
Background:
- Interleukin-6 (IL-6) is a cytokine involved in inflammation and autoimmune diseases.
- IL-6 exerts context-dependent effects through cis-signaling and trans-signaling pathways.
- Current therapies targeting IL-6 broadly affect both pro- and anti-inflammatory signaling, limiting efficacy.
Purpose of the Study:
- To develop a novel strategy for specifically targeting pro-inflammatory IL-6 trans-signaling.
- To avoid interfering with beneficial IL-6 cis-signaling.
- To explore a new gene therapy platform for chronic inflammatory diseases.
Main Methods:
- Developed splice switching oligonucleotides (SSO) to modulate alternative splicing of the GP130 gene.
- Induced expression of truncated, soluble GP130 isoforms that decoy IL-6/sIL-6R complexes.
- Utilized Pip6a cell-penetrating peptide conjugated to PMO-based SSO for in vivo delivery.
Main Results:
- Successfully decoyed IL-6/sIL-6R complexes, specifically inhibiting trans-signaling.
- Demonstrated reduced disease phenotypes in mouse models of systemic and intestinal inflammation.
- Confirmed efficient in vivo delivery of the SSO-based gene therapy.
Conclusions:
- This novel gene therapy platform offers a precise method to target IL-6 trans-signaling.
- The approach effectively suppresses inflammation without disrupting essential IL-6 cis-signaling.
- Holds significant therapeutic potential for treating chronic inflammatory conditions.
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