Key result
Locked nucleic acid-based splice-switching oligonucleotides induced a soluble TNFR2 decoy receptor that antagonized TNF-α and altered disease in hepatitis and arthritis mouse models.
Why the study?
Does LNA-based SSO targeting TNFR2 pre-mRNA reduce inflammation in mouse models of hepatitis and arthritis?
Does LNA-based SSO targeting TNFR2 pre-mRNA reduce inflammation in mouse models of hepatitis and arthritis?
LNA-based SSOs can induce an endogenous circulating TNF-α antagonist by modulating splicing, effectively reducing inflammation in preclinical models of hepatitis and arthritis.
Hypothesis-generating for endogenous TNF-α antagonism; leaves open translation of LNA SSOs to human inflammatory disease.
Tumor necrosis factor-α (TNF-α) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti–TNF-α drugs such as etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are a new class of drugs designed to induce therapeutically favorable splice variants of targeted genes. In this work, we used locked nucleic acid (LNA)–based SSOs to modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous expression from the membrane-bound, functional form to a soluble, secreted form (Δ7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-α, and altered disease in two mouse models: TNF-α-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-α antagonist by oligonucleotide-induced splicing modulation. Tumor necrosis factor-α (TNF-α) is a key mediator of inflammatory diseases, including rheumatoid arthritis (RA), and anti–TNF-α drugs such as etanercept are effective treatments. Splice-switching oligonucleotides (SSOs) are a new class of drugs designed to induce therapeutically favorable splice variants of targeted genes. In this work, we used locked nucleic acid (LNA)–based SSOs to modulate splicing of TNF receptor 2 (TNFR2) pre-mRNA. The SSO induced skipping of TNFR2 exon 7, which codes the transmembrane domain (TM), switching endogenous expression from the membrane-bound, functional form to a soluble, secreted form (Δ7TNFR2). This decoy receptor protein accumulated in the circulation of treated mice, antagonized TNF-α, and altered disease in two mouse models: TNF-α-induced hepatitis and collagen-induced arthritis (CIA). This is the first report of upregulation of the endogenous, circulating TNF-α antagonist by oligonucleotide-induced splicing modulation.
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Graziewicz et al. (2008) studied TNF-α-induced hepatitis and collagen-induced arthritis. Locked nucleic acid (LNA)-based splice-switching oligonucleotides (SSOs) was evaluated on Disease alteration in hepatitis and arthritis models. Locked nucleic acid-based splice-switching oligonucleotides induced a soluble TNFR2 decoy receptor that antagonized TNF-α and altered disease in hepatitis and arthritis mouse models.
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