MicroRNA inhibition for the treatment of inflammation and myeloproliferative disorders
The present disclosure relates to the finding that microRNA-155 plays a role in inflammation, hematopoiesis and myeloproliferation, and that dysregulation of microRNA-155 expression is associated with particular myeloproliferative disorders. Disclosed herein are methods and compositions for diagnosing an treating disorders, including inflammation and myeloproliferation, modulating the levels of expression of one or more genes selected from the group consisting of Cutl1, Arntl, Picalm, Jarid2, PU.1, Csflr, HIF1α, Sla, Cepbβ, and Bach1, and the like.
1. A method of modulating the expression of Bach1 gene in a subject having or suspected of suffering from inflammation or an inflammatory-related condition, comprising:
administering to the subject an miR-155 antisense compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides in an amount effective to modulate the expression of Bach1 gene, wherein the nucleobase sequence of the modified oligonucleotides is complementary to a sequence at least 90% identical to mature microRNA-155 (SEQ ID NO: 73).
2. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide has no more than two mismatches to the nucleobase sequence of mature miR-155 (SEQ ID NO: 73).
3. The method of claim 1 , wherein the modified oligonucleotide comprises a sequence fully complementary to the sequence of mature miR-155 (SEQ ID NO: 73).
4. The method of claim 1 , wherein the modified oligonucleotide comprises at least 15 contiguous nucleobases of SEQ ID NO: 74.
5. The method of claim 4 , wherein the modified oligonucleotide comprises SEQ ID NO: 74.
6. The method of claim 1 , wherein the modified oligonucleotide comprises at least one sugar-modified nucleoside.
7. The method of claim 6 , wherein the sugar-modified nucleoside comprises a modified sugar selected from a bicyclic sugar moiety, a 2′-fluoro sugar, a 2′-O-methyl sugar, and a 2′-O-methoxyethyl sugar.
8. The method of claim 1 , wherein the inflammation is inflammation arising from a macrophage-induced inflammatory response.
9. The method of claim 1 , wherein the inflammation is mediated by a Toll-like receptor (TLR).
10. The method of claim 9 , wherein said TLR is selected from the group consisting of TLR2, TLR3, TLR, 4 and TLR9.
11. The method of claim 1 , wherein the inflammation or inflammatory-related condition is caused by cancer, viral infection or microbial infection.
12. The method of claim 1 , wherein the inflammation or inflammatory-related condition is selected from sepsis, septic shock, neurodegeneration, neutrophilic alveolitis, asthma, hepatitis, inflammatory bowel disease, ischemia, glomerulonephritis, rheumatoid arthritis and Crohn's disease.
13. The method of claim 1 , wherein the subject is human.
14. The method of claim 1 , wherein administration comprises parenteral administration.
15. The method of claim 1 , comprising administering at least one therapy in addition to the miR-155 antisense compound.
16. The method of claim 15 , wherein the additional therapy comprises an immunosuppressant.
17. The method of claim 16 , wherein the immunosuppressant is a corticosteroid.
18. The method of claim 15 , wherein the additional therapy comprises a pharmaceutical agent that enhances the body's immune system.
19. The method of claim 18 , wherein the pharmaceutical agent is selected from low-dose cyclophosphamide, thymostimulin, vitamins, nutritional supplements and vaccines.
20. The method of claim 1 , wherein the modified oligonucleotide consists of 15 to 25 linked nucleosides.