Modulators of PCSK9 Expression

Abstract

The present embodiments provide methods, compounds, and compositions useful for inhibiting PCSK9 expression, which may be useful for treating, preventing, or ameliorating a disease associated with PCSK9.

1 - 66 . (canceled) 
     
     
         67 . A compound or a pharmaceutically acceptable salt thereof, comprising a modified oligonucleotide 12 to 30 linked nucleosides in length having a nucleobase sequence comprising at least 12 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 1016. 
     
     
         68 . The compound of  claim 67 , wherein at least one of the nucleosides of the modified oligonucleotide comprises a cEt sugar. 
     
     
         69 . The compound of  claim 67 , wherein the modified oligonucleotide comprises
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of three linked nucleosides; and   a 3′ wing segment consisting of three linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; wherein the 5′ wing segment and the 3′ wing segment comprise cEt sugars; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine.   
     
     
         70 . The compound of  claim 67 , further comprising a conjugate group and a conjugate linker. 
     
     
         71 . The compound of  claim 71 , wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide. 
     
     
         72 . The compound of  claim 71 , wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide. 
     
     
         73 . The compound of  claim 72 , wherein the conjugate group is 5′-Trishexylamino-(THA)-C6GalNAC3. 
     
     
         74 . The compound of  claim 67 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         75 . The compound of  claim 67 , wherein the pharmaceutically acceptable salt is a potassium salt. 
     
     
         76 . A pharmaceutical composition comprising the compound of  claim 67 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         77 . A pharmaceutical composition comprising the sodium salt of  claim 74 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         78 . A pharmaceutical composition comprising the potassium salt of  claim 75 , and a pharmaceutically acceptable diluent or carrier. 
     
     
         79 . A method of treating, preventing, or ameliorating a disease associated with PCSK9 in an individual comprising administering to the individual a compound of  claim 67 . 
     
     
         80 . The method of  claim 79 , wherein the disease is selected from hypercholesterolemia, dyslipidemia or mixed dyslipidemia. 
     
     
         81 . The method of  claim 79 , wherein administering the compound inhibits or reduces LDL-cholesterol levels and total cholesterol levels and improves the induction of hepatic LDL receptor levels. 
     
     
         82 . A method of inhibiting expression of PCSK9 in a cell comprising contacting the cell with a compound of  claim 67 . 
     
     
         83 . The method of  claim 82 , wherein the cell is in the liver of an individual. 
     
     
         84 . The method of  claim 83 , wherein the individual has, or is at risk of having, hypercholesterolemia, dyslipidemia, or mixed dyslipidemia. 
     
     
         85 . A method of reducing or inhibiting LDL-cholesterol levels and total cholesterol levels in an individual having, or at risk of having, a disease associated with PCSK9 comprising administering a compound of  claim 67 . 
     
     
         86 . The method of  claim 85 , wherein the individual has, or is at risk of having, hypercholesterolemia, dyslipidemia, or mixed dyslipidemia.