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 .- 51 . (canceled) 
     
     
         52 . A compound comprising a modified oligonucleotide of the structure: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                 
                     
                   T E   Me C E A E A E C S A E T E C S A E G E T E C S T E G E A E U S A E A E G E C S T E A E   
                 
             
                
                
               
            
           
         
         wherein nucleosides followed by a subscript “E” are 2′-O-methoxyethyl (2′-MOE) nucleosides, nucleosides followed by a subscript “S” are S-constrained ethyl (S-cET) nucleosides, and nucleosides followed by a superscript “Me” have a 5-methyl group on the pyrimidine base of the nucleoside, and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
       
     
     
         53 . The compound of  claim 52 , wherein the modified oligonucleotide is conjugated to one or more moieties that enhance activity, cellular distribution, or cellular uptake. 
     
     
         54 . The compound of  claim 52 , wherein the modified oligonucleotide is conjugated to a moiety selected from a lipid, cholesterol, a carbohydrate, a phospholipid, biotin, phenazine, and folate. 
     
     
         55 . A pharmaceutical composition comprising the compound of  claim 52  and a pharmaceutically acceptable carrier. 
     
     
         56 . A method of inhibiting the activity of miR-21 comprising contacting a cell with the compound of  claim 52 . 
     
     
         57 . The method of  claim 56 , wherein the cell is in vivo or wherein the cell is in vitro. 
     
     
         58 . The method of  claim 56 , wherein the cell is a fibroblast cell, a hyperproliferative cell, a keratinocyte, or a hypoxic cell. 
     
     
         59 . A method of decreasing collagen expression in a cell comprising contacting a cell with the compound of  claim 52 . 
     
     
         60 . 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 the compound of  claim 52 . 
     
     
         61 . The method of  claim 60 , wherein the disease is fibrosis. 
     
     
         62 . The method of  claim 61 , 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. 
     
     
         63 . The method of  claim 62 , 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, 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.   
     
     
         64 . The method of  claim 61 , 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. 
     
     
         65 . The method of  claim 61 , 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. 
     
     
         66 . The method of  claim 61 , 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. 
     
     
         67 . The method of  claim 60 , wherein the disease is cancer. 
     
     
         68 . The method of  claim 67 , 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. 
     
     
         69 . The method of  claim 67 , further comprising administering at least one additional anti-cancer therapy to the subject. 
     
     
         70 . A method of treating a fibroproliferative disorder in a subject comprising administering to the subject the compound of  claim 52 . 
     
     
         71 . The method of  claim 60 , wherein the subject is a human.