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 consisting of 20 to 30 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO: 1 over the entire length of the modified oligonucleotide, wherein a portion of the modified oligonucleotide comprises at least 8 contiguous nucleobases complementary to an equal length portion of nucleobases 3543-3562 of SEQ ID NO: 1, and wherein the modified oligonucleotide comprises at least one modified sugar and/or at least one modified internucleoside linkage.
2. The compound of claim 1 , wherein the compound is single-stranded.
3. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one internucleoside linkage which is a phosphorothioate internucleoside linkage.
4. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.
5. The compound of claim 4 , wherein at least one modified sugar is a bicyclic sugar.
6. The compound of claim 4 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl.
7. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
8. The compound of claim 7 , wherein the modified nucleobase is a 5-methylcytosine.
9. 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.
10. The compound of claim 9 , 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.
11. The compound of claim 1 , wherein the modified oligonucleotide is 20 linked nucleosides in length.
12. A composition comprising the compound of claim 1 or a salt thereof and a pharmaceutically acceptable carrier or diluent.
13. A method comprising administering the compound of claim 1 to an animal having, or at risk of having, a disease associated with PCSK9.
14. The method of claim 13 , wherein the animal is a human.
15. The method of claim 13 , 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.
16. The method of claim 13 comprising co-administering the compound and at least one additional therapy.
17. The method of claim 13 , wherein the administering is parenteral administration.
18. The compound of claim 4 , wherein at least one modified sugar comprises a 2′-fluoro or 2′-O-methyl.