MicroRNA Compounds and Methods for Modulating MIR-21 Activity

Abstract

Described herein are compositions and methods for the inhibition of miR-21 activity. The compositions have certain nucleoside modification patterns that yield potent inhibitors of miR-21 activity. The compositions may be used to inhibit miR-21, and also to treat diseases associated with abnormal expression of miR-21, such as fibrosis and cancer.

1 .- 34 . (canceled) 
     
     
         35 . A method of inhibiting the activity of miR-21 comprising contacting a cell with a compound comprising a modified oligonucleotide having the structure:
 A E C S A E T E C S A E G E T E C S TGAU S AAGC S U S A S  (SEQ ID NO: 3);   wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides;   nucleosides followed by a subscript “E” are 2′-MOE nucleosides; and nucleosides followed by a subscript “S” are S-cEt nucleosides.   
     
     
         36 . The method of  claim 35 , wherein the cell is in vivo or wherein the cell is in vitro. 
     
     
         37 . The method of  claim 35  wherein the cell is a fibroblast cell, a hyperproliferative cell, a keratinocyte, or a hypoxic cell. 
     
     
         38 . A method of decreasing collagen expression in a cell comprising contacting a cell with a compound comprising a modified oligonucleotide having the structure:
 A E C S A E T E C S A E G E T E C S TGAU S AAGC S U S A S  (SEQ ID NO: 3);   wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides;   nucleosides followed by a subscript “E” are 2′-MOE nucleosides; and nucleosides followed by a subscript “S” are S-cEt nucleosides.   
     
     
         39 . A method of treating, preventing or delaying the onset of a disease associated with miR-21 comprising administering to a subject having a disease associated with miR-21 a compound comprising a modified oligonucleotide having the structure:
 A E C S A E T E C S A E G E T E C S TGAU S AAGC S U S A S  (SEQ ID NO: 3);   wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides;   nucleosides followed by a subscript “E” are 2′-MOE nucleosides; and nucleosides followed by a subscript “S” are S-cEt nucleosides.   
     
     
         40 . The method of  claim 39 , wherein the disease is fibrosis. 
     
     
         41 . The method of  claim 40 , wherein the fibrosis is selected from kidney fibrosis, lung fibrosis, liver fibrosis, cardiac fibrosis, skin fibrosis, age-related fibrosis, spleen fibrosis, scleroderma, and post-transplant fibrosis. 
     
     
         42 . The method of  claim 41 , wherein:
 a. the kidney fibrosis is present in a subject having a disease selected from glomerulosclerosis, tubulointerstitial fibrosis, IgA nephropathy, interstitial fibrosis/tubular atrophy; chronic kidney damage, glomerular disease, glomerulonephritis, Alport Syndrome, diabetes mellitus, idiopathy focal segmental glomerulosclerosis, membranous nephropathy, collapsing glomerulopathy, chronic recurrent kidney infection, and end stage renal disease;   b. the kidney fibrosis results from acute or repetitive trauma to the kidney;   c. the liver fibrosis is present in a subject having a disease selected from chronic liver injury, hepatitis infection, non-alcoholic steatohepatitis, and cirrhosis;   d. the pulmonary fibrosis is idiopathic pulmonary fibrosis; and/or   e. the subject has chronic obstructive pulmonary disease.   
     
     
         43 . The method of  claim 39 , wherein the disease associated with miR-21 is a fibroproliferative disorder. 
     
     
         44 . The method of  claim 39  comprising selecting a subject having elevated miR-21 expression in one or more tissues. 
     
     
         45 . The method of  claim 40  wherein the subject is in need of improved organ function, wherein the organ function is selected from cardiac function, pulmonary function, liver function, and kidney function. 
     
     
         46 . The method of  claim 45  wherein the administering improves organ function in the subject, wherein the organ function is selected from cardiac function, pulmonary function, liver function, and kidney function. 
     
     
         47 . The method of  claim 40  comprising administering at least one therapeutic agent 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. 
     
     
         48 . The method of  claim 39 , wherein the disease is cancer. 
     
     
         49 . The method of  claim 48 , wherein the cancer is liver cancer, breast cancer, bladder cancer, prostate cancer, colon cancer, lung cancer, brain cancer, hematological cancer, pancreatic cancer, head and neck cancer, cancer of the tongue, stomach cancer, skin cancer, or thyroid cancer. 
     
     
         50 . The method of  claim 48 , further comprising administering at least one additional anti-cancer therapy to the subject. 
     
     
         51 . The method of  claim 39 , wherein the subject is a human. 
     
     
         52 . The method of  claim 39 , wherein the compound is present as a pharmaceutical composition. 
     
     
         53 .- 65 . (canceled)