METHODS FOR TREATING HYPERCHOLESTEROLEMIA
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)