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 of 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, and wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage; and wherein the fibrosis is kidney fibrosis.
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 kidney fibrosis results from one or more of a disease selected from 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, and end stage renal disease.
5. The method of claim 1 , wherein the kidney fibrosis results from acute kidney injury, chronic kidney injury, surgery, chemotherapy, radiation treatment, allograft rejection, chronic transplant rejection, or acute transplant rejection.
6. The method of claim 1 , comprising improving one or more symptoms of fibrosis.
7. The method of claim 1 , wherein the administering:
a. prevents progression of fibrosis
b. delays the progression of 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 the nucleobase sequence of SEQ ID NO: 1.
12. 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.
13. 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.
14. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide comprises a nucleobase sequence that is fully complementary to nucleobases 2-8 of SEQ ID NO: 1.
15. The method of claim 1 , wherein each nucleoside of the modified oligonucleotide comprises a modified sugar moiety.
16. The method of claim 15 , 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.