The present invention provides an oligonucleotide which is capable of activating RIG-I and inducing an anti-viral, in particular, an IFN, response in cells expressing RIG-I. The present invention further provides an oligonucleotide which is capable of activating RIG-I and which has target gene-silen
The present invention provides an oligonucleotide which is capable of activating RIG-I and inducing an anti-viral, in particular, an IFN, response in cells expressing RIG-I. The present invention further provides an oligonucleotide which is capable of activating RIG-I and which has target gene-silencing activity. The oligonucleotide of the present invention has a double-stranded section of at least 19, preferably at least 21 bp, at least one 5′ triphosphate, and at least one blunt end which bears a 5′ triphosphate. The present invention further provides the use said oligonucleotide for inducing an anti-viral, in particular, an IFN, response in vitro and in vivo. The present invention additionally provides the use of said oligonucleotide for preventing and/or treating diseases or conditions such as infections, tumors/cancers, and immune disorders.
대표청구항▼
1. An oligonucleotide preparation comprising an essentially homogenous population of an oligonucleotide, wherein the oligonucleotide has two blunt ends each bearing a 5′ triphosphate,wherein the oligonucleotide comprises at least 1 ribonucleotide at the 5′ end at the blunt ends,wherein the 5′ tripho
1. An oligonucleotide preparation comprising an essentially homogenous population of an oligonucleotide, wherein the oligonucleotide has two blunt ends each bearing a 5′ triphosphate,wherein the oligonucleotide comprises at least 1 ribonucleotide at the 5′ end at the blunt ends,wherein the 5′ triphosphate is free of any cap structure,wherein each blunt end is an end of a fully double-stranded section, andwherein the fully double-stranded section is at least 19 base pairs in length. 2. The oligonucleotide preparation of claim 1, wherein the double-stranded section is at least 21 base pairs in length. 3. The oligonucleotide preparation of claim 1, wherein the double-stranded section has a length selected from 21, 22, 23, 24, 25, 26, or at least 30 to at most 60 bp in length. 4. The oligonucleotide preparation of claim 1, wherein the oligonucleotide comprises at least one inosine. 5. The oligonucleotide preparation of claim 1, wherein the most 5′ ribonucleotide with the triphosphate attached thereto is selected from the group consisting of A, G and U. 6. The oligonucleotide preparation of claim 1, wherein the sequence of the first 4 ribonucleotides at the 5′ end bearing the 5′-triphosphate is selected from the group consisting of: AAGU, AAAG, AUGG, AUUA, AACG, AUGA, AGUU, AUUG, AACA, AGAA, AGCA, AACU, AUCG, AGGA, AUCA, AUGC, AGUA, AAGC, AACC, AGGU, AAAC, AUGU, ACUG, ACGA, ACAG, AAGG, ACAU, ACGC, AAAU, ACGG, AUUC, AGUG, ACAA, AUCC, AGUC, wherein the sequence is in the 5′→3′ direction. 7. The oligonucleotide preparation of claim 1, wherein the oligonucleotide is free of modifications selected from the group consisting of pseudouridine, 2-thiouridine, 2′-fluorine-dNTP. 8. The oligonucleotide preparation of claim 1, wherein the most 3′ nucleotide which base pairs with the most 5′ ribonucleotide bearing the 5′ triphosphate at the blunt end is 2′-O-methylated. 9. The oligonucleotide preparation of claim 1, wherein the oligonucleotide comprises at least one structural motif recognized by at least one of TLR3, TLR7, TLR8 and TLR9. 10. The oligonucleotide preparation of claim 1, wherein the oligonucleotide has target gene-silencing activity. 11. The oligonucleotide preparation of claim 10, wherein the oligonucleotide has both target gene-silencing activity and the ability of RIG-I activation. 12. The oligonucleotide preparation of claim 10, wherein the target gene is Bcl-2. 13. The oligonucleotide preparation of claim 1, wherein the oligonucleotide comprises phosphorothioate linkage(s) and/or pyrophosphate linkage(s). 14. A pharmaceutical composition comprising at least one oligonucleotide preparation of claim 1 and a pharmaceutically acceptable carrier. 15. The pharmaceutical composition of claim 14, further comprising an immunostimulatory agent, an antigen, an anti-viral agent, an anti-bacterial agent, an anti-tumor agent, retinoic acid, IFN-α, IFN-β, or any combination thereof. 16. An in vitro method for inducing type I IFN production in a cell, comprising the steps of: (a) mixing at least one oligonucleotide preparation of claim 1 with a complexation agent; and(b) contacting a cell with the mixture of (a), wherein the cell expresses RIG-I. 17. A method for treating a disease selected from a tumor, an infection, and an immune disorder in a subject, the method comprising the step of administering a pharmaceutical composition as defined in claim 14 to said subject. 18. The method of claim 17, wherein the pharmaceutical composition is administered in combination with a therapeutic treatment of a tumor, an infection or an immune disorder. 19. The method of claim 17, wherein the oligonucleotide preparation is administered in combination with an immunostimulatory agent, an antigen, an anti-viral agent, an anti-bacterial agent, an anti-tumor agent, retinoic acid. IFN-α, IFN-β, or any combination thereof.
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