Methods and compositions for inhibition of immune responses and autoimmunity
The application relates to the use of immunoregulatory polynucleotides and/or immunoregulatory compounds in combination with other therapeutic agents. The application further relates to immunoregulatory polynucleotides and/or immunoregulatory compounds comprising a modified immunoregulatory sequence. It also relates to the administration of the immunoregulatory polynucleotides and/or immunoregulatory compounds comprising a modified immunoregulatory sequence to regulate an immune response.
1. A polynucleotide consisting of a nucleotide sequence of the formula: 5′-N n UGCN m -3′, wherein 5′-UGC-3′ is a TLR7-inhibitory sequence located at or 1 nucleotide from the 5′ end of the polynucleotide, each N is a nucleotide, n is 0 or 1, m is an integer from 5 to 50, and N m comprises 5′-S 1 S 2 S 3 S 4 -3′, wherein 5′-S 1 S 2 S 3 S 4 -3′ is a TLR9-inhibitory sequence, at least one of S 1 , S 2 , S 3 , and S 4 is inosine, wherein remaining S 1 , S 2 , S 3 , and S 4 , if any, are G, and wherein the polynucleotide does not comprise a CG dinucleotide.
2. A method of inhibiting an immune response in an individual, comprising administering to the individual the polynucleotide of claim 1 in an amount sufficient to inhibit an immune response in the individual.
3. The method of claim 2 , wherein the immune response comprises a TLR7 dependent immune response.
4. The method of claim 2 , wherein the immune response is a TLR9 dependent immune response and/or TLR7 dependent immune response.
5. The method of claim 2 , wherein the immune response is associated with an autoimmune disease.
6. The method of claim 5 , wherein inhibiting the immune response ameliorates one or more symptoms of the autoimmune disease.
7. The method of claim 5 , wherein inhibiting the immune response prevents or delays development of the autoimmune disease.
8. The method of claim 5 , wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), autoimmune skin disease and rheumatoid arthritis.
9. The method of claim 2 , wherein the immune response is associated with chronic pathogen stimulation.
10. A kit comprising the polynucleotide of claim 1 in a suitable container and instructions for use of the polynucleotide in inhibiting an immune response in an individual.
11. The method of claim 2 , wherein the immune response is associated with drug-induced inflammation of the liver, or pancreatitis.
12. The method of claim 2 , wherein the individual is a human.
13. The method of claim 5 , further comprising administering a corticosteroid to the individual.
14. The polynucleotide of claim 1 , wherein the sequence 5′-N n UGCN m -3′ comprises a modification, wherein said modification comprises a modified base, a modified sugar, and/or a modified phosphate.
15. The polynucleotide of claim 14 , wherein said modified phosphate comprises a methyl phosphonate, a phosphorothioate, a phosphoroamidate, a phosphotriester, and/or a phosphorodithioate modification.
16. The polynucleotide of claim 15 , wherein said modified phosphate is a phosphorothioate modification.
17. The polynucleotide of claim 16 , wherein each nucleotide N comprises the phosphorothioate modification.
18. The polynucleotide of claim 14 , wherein said modified sugar is a 2′-sugar modification.
19. The polynucleotide of claim 18 , wherein said 2′-sugar modification is a 2′-O-methyl sugar modification or a 2′-O-methoxyethyl sugar modification.
20. The polynucleotide of claim 14 , wherein said modified base is a 5′-methyl-cytosine modification.
21. The polynucleotide of claim 1 , wherein the 5′-UGC-3′ is located 1 nucleotide from the 5′ end of the polynucleotide.
22. The polynucleotide of claim 1 , wherein the 5′-UGC-3′ is located at the 5′ end of the polynucleotide.
23. The polynucleotide of claim 1 , wherein two, three or four of S 1 , S 2 , S 3 , and S 4 are inosine.
24. The polynucleotide of claim 1 , wherein inosine is deoxyinosine.
25. The polynucleotide of claim 1 , wherein N m comprises a non-nucleic acid spacer moiety.
26. The polynucleotide of claim 25 , wherein the non-nucleic acid spacer moiety comprises hexa-(ethylene glycol).
27. The polynucleotide of claim 1 , wherein only one of S 1 , S 2 , S 3 , and S 4 is inosine.
28. The polynucleotide of claim 27 , wherein inosine is deoxyinosine.
29. The polynucleotide of claim 28 , wherein 5′-S 1 S 2 S 3 S 4 -3′ is 5′-GIGG-3′.
30. The polynucleotide of claim 1 , wherein said polynucleotide is single-stranded DNA.
31. The polynucleotide of claim 1 , wherein said polynucleotide is double-stranded DNA.
32. The polynucleotide of claim 29 , wherein said polynucleotide is single-stranded DNA.
33. A pharmaceutical composition comprising the polynucleotide of claim 1 and a pharmaceutically acceptable excipient.
34. A pharmaceutical composition comprising the polynucleotide of claim 29 and a pharmaceutically acceptable excipient.
35. The polynucleotide of claim 32 , wherein said polynucleotide is selected from the group consisting of SEQ ID NO:173, SEQ ID NO:175, SEQ ID NO:176, SEQ ID NO:177, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:180, SEQ ID NO:181, and SEQ ID NO:186.
36. A pharmaceutical composition comprising the polynucleotide of claim 35 and a pharmaceutically acceptable excipient.
37. The pharmaceutical composition of claim 36 , wherein the polynucleotide is less than 25 bases in length.