Targeting microRNAs for the treatment of fibrosis
Provided herein are compositions and methods for the modulation of miR-214 for the treatment and/or prevention of fibrosis and fibroproliferative conditions.
1. A method of treating, preventing, or delaying the onset of fibrosis comprising
administering to a subject having fibrosis or at risk for developing fibrosis a compound comprising a modified oligonucleotide consisting of 8 to 12 linked nucleosides, and having a nucleobase sequence that is fully complementary to the nucleobase sequence of miR-214.
2. The method of claim 1 comprising selecting a subject having fibrosis.
3. The method of claim 1 comprising selecting a subject at risk for developing fibrosis.
4. The method of claim 1 , wherein the fibrosis is kidney fibrosis, liver fibrosis, cardiac fibrosis, pulmonary fibrosis, restenosis-related vascular fibrosis, spleen fibrosis, age-related fibrosis, skin fibrosis, or post-transplantation fibrosis.
5. The method of claim 4 , wherein the kidney fibrosis results from one or more of tubulointerstitial fibrosis, IgA nephropathy, interstitial fibrosis/tubular atrophy; chronic kidney damage, glomerular disease, glomerulonephritis, diabetes mellitus, idiopathy focal segmental glomerulosclerosis, membranous nephropathy, collapsing glomerulopathy, chronic recurrent kidney infection, end stage renal disease, acute kidney injury, chronic kidney injury, surgery, chemotherapy, radiation treatment, allograft rejection, chronic transplant rejection, or acute transplant rejection.
6. The method of claim 4 wherein the liver fibrosis is present in a subject having a disease selected from chronic liver injury, hepatitis infection, non-alcoholic steatohepatitis, and cirrhosis.
7. The method of claim 1 wherein the administering:
a) prevents progression of the fibrosis;
b) delays the progression of the fibrosis; and/or
c) reduces the fibrosis.
8. The method of claim 1 comprising administering at least one additional therapeutic agent.
9. The method of claim 8 wherein the at least one additional therapeutic agent is selected from an anti-inflammatory agent, an immunosuppressive agent, an anti-diabetic agent, digoxin, a vasodilator, an angiotensin II converting enzyme (ACE) inhibitors, an angiotensin II receptor blockers (ARB), a calcium channel blocker, an isosorbide dinitrate, a hydralazine, a nitrate, a hydralazine, a beta-blocker, a natriuretic peptides, a heparinoid, and a connective tissue growth factor inhibitor.
10. The method of claim 1 , wherein the compound consists of the modified oligonucleotide.
11. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is fully complementary to a nucleobase sequence selected from SEQ ID NO: 1 and 2.
12. The method of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.
13. The method of claim 1 , wherein the modified oligonucleotide comprises at least one nucleoside comprising a modified sugar, wherein each modified sugar is independently selected from a 2′-O-methoxyethyl sugar, a 2′-fluoro sugar, 2′-O-methyl sugar, and a bicyclic sugar moiety.
14. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises a nucleobase sequence that is fully complementary to nucleobases 2-7 of SEQ ID NO: 1.
15. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises a nucleobase sequence that is fully complementary to nucleobases 2-8 of SEQ ID NO: 1.
16. The method of claim 1 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety.
17. The method of claim 16 , wherein each modified sugar is independently selected from a 2′-O-methoxyethyl sugar, a 2′-fluoro sugar, 2′-O-methyl sugar, and a bicyclic sugar moiety.
18. The method of claim 12 , wherein the modified nucleoside linkage is a phosphorothioate internucleoside linkage.