Compounds and methods for reducing fxi expression

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of FXI RNA in a cell or subject, and in certain instances reducing the amount of FXI protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to prevent, treat, or ameliorate at least one symptom of a thromboembolic condition without a significant increase in a bleeding risk. Such thromboembolic conditions include deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition. Such symptoms include decreased blood flow through an affected vessel, death of tissue, and death.

1 . An oligomeric compound according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         2 . An oligomeric compound according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         3 . (canceled) 
     
     
         4 . An oligomeric compound according to the following formula:
 (THA-GalNAc 3 )o Aes mCeo Geo Geo mCeo Ads Tds Tds Gds Gds Tds Gds mCds Ads mCds Aeo Geo Tes Tes Te (SEQ ID NO: 3); wherein, (THA-GalNAc 3 )o is represented by the following chemical structure:   
       
         
           
           
               
               
           
         
       
       and wherein,
 A=an adenine nucleobase, 
 mC=a 5′-methyl cytosine nucleobase, 
 G=a guanine nucleobase, 
 T=a thymine nucleobase, 
 e=a 2′-MOE modified sugar, 
 d=a 2′-deoxyribose sugar, 
 s=a phosphorothioate internucleoside linkage, and 
 o=a phosphodiester internucleoside linkage; 
 or a salt thereof. 
 
     
     
         5 . The oligomeric compound of  claim 1 , which is a sodium salt. 
     
     
         6 . A chirally enriched population of the oligomeric compound of  claim 1 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration. 
     
     
         7 . The chirally enriched population of  claim 6 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration. 
     
     
         8 . The chirally enriched population of  claim 6 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration. 
     
     
         9 . The chirally enriched population of  claim 6 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage. 
     
     
         10 . The chirally enriched population of  claim 9 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide having the (Sp) configuration at each phosphorothioate internucleoside linkage. 
     
     
         11 . The chirally enriched population of  claim 9 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide having the (Rp) configuration at each phosphorothioate internucleoside linkage. 
     
     
         12 . The chirally enriched population of  claim 9 , wherein the population is enriched for oligomeric compounds having a modified oligonucleotide having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp-Sp-Rp configurations, in the 5′ to 3′ direction. 
     
     
         13 . A population of oligomeric compounds having a modified oligonucleotide of  claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         14 . A pharmaceutical composition comprising the oligomeric compound of  claim 1 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutically acceptable diluent is phosphate buffered saline. 
     
     
         16 . The pharmaceutical composition of  claim 14 , wherein the pharmaceutical composition consists or consists essentially of the oligomeric compound and phosphate buffered saline. 
     
     
         17 - 63 . (canceled) 
     
     
         64 . A pharmaceutical composition comprising the oligomeric compound of  claim 2 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         65 . The pharmaceutical composition of  claim 64 , wherein the pharmaceutically acceptable diluent is phosphate buffered saline. 
     
     
         66 . The pharmaceutical composition of  claim 64 , wherein the pharmaceutical composition consists or consists essentially of the oligomeric compound and phosphate buffered saline.