Methods of treatment using TLR7 and/or TLR9 inhibitors
The application relates to compositions and methods of regulating an immune response comprising inhibitors of TLR7 and/or TLR9, such as immunoregulatory polynucleotides and/or immunoregulatory compounds. The application also relates to compositions and methods for predicting and/or determining responsiveness of a disease to treatment comprising inhibitors of TLR7 and/or TLR9.
1. A polynucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO:73, SEQ ID NO:134, SEQ ID NO:143 and SEQ ID NO:144, wherein the polynucleotide is less than 100 bases or base pairs in length.
2. The polynucleotide of claim 1 , wherein the polynucleotide consists of the nucleotide sequence selected from the group consisting of SEQ ID NO:73, SEQ ID NO:134, SEQ ID NO:143 and SEQ ID NO:144.
3. The polynucleotide of claim 2 , wherein one or more nucleotides comprises a modification.
4. The polynucleotide of claim 3 , wherein the modification comprises at least one phosphorothioate backbone modification.
5. The polynucleotide of claim 3 , wherein the modification comprises a 2′-sugar modification.
6. The polynucleotide of claim 5 , wherein the 2′-sugar modification comprises a 2′-O-methyl sugar modification or a 2′-O-methoxyethyl sugar modification.
7. The polynucleotide of claim 1 , wherein the polynucleotide is less than 50 bases or base pairs in length.
8. The polynucleotide of claim 1 , wherein the polynucleotide does not comprise a CG dinucleotide.
9. A method of treating an autoimmune disease, comprising administering to an individual having an autoimmune disease an effective amount of the polynucleotide of claim 1 .
10. The method of claim 9 , wherein the polynucleotide is administered in an amount effective to achieve one or more of the following outcomes:
a) reduce a clinical disease activity measure of the autoimmune disease;
b) reduce a serologic disease measure of the autoimmune disease; and
c) increase plasmacytoid dendritic cells in a post-treatment peripheral blood mononuclear cell sample from the individual.
11. The method of claim 9 , further comprising administering a second therapeutic agent to the individual.
12. The method of claim 11 , wherein the second therapeutic agent is selected from the group consisting of a corticosteroid, a nonsteroidal anti-inflammatory drug (NSAID), an IFN-alpha inhibitor, and an anti-malarial.
13. The method of claim 12 , wherein the corticosteroid is a glucocorticoid and the administering the polynucleotide is effective in reducing the glucocorticoid use by the individual.
14. The method of claim 9 , wherein the individual is a human.
15. The method of claim 9 , wherein the autoimmune disease is systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE).
16. The polynucleotide of claim 1 , wherein the polynucleotide consists of the nucleotide sequence of SEQ ID NO:73.
17. The polynucleotide of claim 1 , wherein the polynucleotide consists of the nucleotide sequence selected of SEQ ID NO:134.
18. The polynucleotide of claim 1 , wherein the polynucleotide consists of the nucleotide sequence of SEQ ID NO:143.
19. The polynucleotide of claim 1 , wherein the polynucleotide consists of the nucleotide sequence of SEQ ID NO:144.
20. The polynucleotide of claim 1 , wherein the polynucleotide is less than 40 bases or base pairs in length.
21. The polynucleotide of claim 1 , wherein the polynucleotide is less than 30 bases or base pairs in length.
22. The polynucleotide of claim 1 , wherein the polynucleotide is less than 25 bases or base pairs in length.
23. The polynucleotide of claim 1 , wherein the polynucleotide is less than 20 bases or base pairs in length.
24. The polynucleotide of claim 4 , wherein the polynucleotide contains only phosphorothioate linkages.
25. The polynucleotide of claim 1 , wherein the polynucleotide is single stranded.
26. The polynucleotide of claim 1 , wherein the polynucleotide is double stranded.
27. A pharmaceutical composition comprising the polynucleotide of claim 1 and a pharmaceutically acceptable excipient.
28. The pharmaceutical composition of claim 27 comprising a sterile, isotonic solution.
29. The polynucleotide of claim 16 , wherein the polynucleotide contains only phosphorothioate linkages.
30. The polynucleotide of claim 16 , wherein the polynucleotide is single stranded.
31. The polynucleotide of claim 16 , wherein the polynucleotide is single stranded and contains only phosphorothioate linkages.
32. A pharmaceutical composition comprising the polynucleotide of claim 16 and a pharmaceutically acceptable excipient.
33. The pharmaceutical composition of claim 32 comprising a sterile, isotonic solution.