Methods for treating hypercholesterolemia

Abstract

Disclosed herein are antisense compounds and methods for decreasing LDL-C in an individual having elevated LDL-C. Additionally disclosed are antisense compounds and methods for treating, preventing, or ameliorating hypercholesterolemia and/or atherosclerosis. Further disclosed are antisense compounds and methods for decreasing coronary heart disease risk. Such methods include administering to an individual in need of treatment an antisense compound targeted to a PCSK9 nucleic acid. The antisense compounds administered include gapmer antisense oligonucleotides.

1 . A compound comprising a modified oligonucleotide 12 to 30 linked nucleosides in length and having a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal-length portion of nucleobases 3543-3569 of SEQ ID NO: 1, and wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to SEQ ID NO: 1. 
     
     
         2 . The compound of  claim 1 , wherein the modified oligonucleotide is at least 95% complementary to SEQ ID NO: 1. 
     
     
         3 . The compound of  claim 1 , wherein the modified oligonucleotide is 100% complementary to SEQ ID NO: 1. 
     
     
         4 .- 12 . (canceled) 
     
     
         13 . The compound of  claim 1 , wherein the compound is single-stranded. 
     
     
         14 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one internucleoside linkage which is a phosphorothioate internucleoside linkage. 
     
     
         15 . The compound of  claim 14 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         16 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         17 . The compound of  claim 16 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         18 . The compound of  claim 16 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         19 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase. 
     
     
         20 . The compound of  claim 19 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         21 . The compound of  claim 1 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment; and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         22 . The compound of  claim 21 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.   
     
     
         23 . (canceled) 
     
     
         24 . The compound of  claim 2 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         25 . A composition comprising the compound of  claim 1 , or a salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . A method comprising administering the compound of  claim 1  to an animal having, or at risk of having, a disease associated with PCSK9. 
     
     
         29 . The method of  claim 28 , wherein the animal is a human. 
     
     
         30 . The method of  claim 28 , wherein administering the compound to the animal slows progression and/or ameliorates hypercholesterolemia, acute coronary syndrome, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, early onset coronary heart disease, type II diabetes, type II diabetes with dyslipidemia, hepatic steatosis, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, hypertriglyceridemia, hyperfattyacidemia, hyperlipidemia, metabolic syndrome, atherosclerosis, or improves cardiovascular outcome, or any combination thereof in the animal. 
     
     
         31 . The method of  claim 28  comprising co-administering the compound and at least one additional therapy. 
     
     
         32 .- 39 . (canceled) 
     
     
         40 . The method of  claim 28 , wherein the administering is parenteral administration. 
     
     
         41 .- 281 . (canceled)