TLR inhibitory oligonucleotides and their use
The inhibitory oligonucleotides with partial phosphorothioation with reduced toxicity strongly block NF-kB activation induced by TLR9 agonists and TLR7/8 agonists. The production of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFa), is inhibited by the inhibitory-oligonucleotides. Interferon (IFN) production from human PBMC induced by TLR9 agonist is prevented by the inhibitory-oligonucleotides. These oligonucleotides can be used as a remedy for the treatment of immune-mediated disorders such as rheumatoid arthritis, systemic lupus erythematosus (SLE), sepsis, multiple organ dysfunction syndromes and inflammatory cytokine-mediated inflammatory disease.
1. A partially phosphorothioated oligonucleotide, wherein the nucleobase sequence of the oligonucleotide is 5′-CCTCCtCCTCCTCCtCCTCCTCCtCCTCCTCCtCCt-3′ (SEQ ID NO:27), wherein a capital case letter denotes a nucleotide that is phosphorothioate-modified in the internucleotide linkage at 3′, and a lower case letter denotes a nucleotide that is phosphodiester-un-modified in the internucleotide linkage at 3′.
2. The oligonucleotide according to claim 1 , wherein said oligonucleotide comprises an additional chemical modification, wherein the additional chemical modification is other than phosphorothioation.
3. A pharmaceutical composition comprising the oligonucleotide according to claim 1 and a pharmaceutically acceptable carrier.
4. A partially phosphorothioated oligonucleotide, wherein the nucleobase sequence of the oligonucleotide is 5′-TCCTCCTCcTCCTCCTCcTCCTCCTCcTCCTCCTCc-3′ (SEQ ID NO:40), wherein a capital case letter denotes a nucleotide that is phosphorothioate-modified in the internucleotide linkage at 3′, and a lower case letter denotes a nucleotide that is phosphodiester-un-modified in the internucleotide linkage at 3′.
5. The oligonucleotide according to claim 4 , wherein said oligonucleotide comprises an additional chemical modification, wherein the additional chemical modification is other than phosphorothioation.
6. A pharmaceutical composition comprising the oligonucleotide according to claim 4 and a pharmaceutically acceptable carrier.