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 method of reducing PCSK9 expression in an animal comprising administering to the animal a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to region 3472-3562 of SEQ ID NO: 1, wherein the compound reduces PCSK9 expression by at least 30% in the animal.
2. The method of claim 1 , wherein PCSK9 expression is reduced by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.
3. The method of claim 1 , wherein reducing PCSK9 expression in the animal treats hypercholesterolemia, polygenic hypercholesterolemia, mixed dyslipidemia, coronary heart disease, acute coronary syndrome, 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, elevated ApoB, elevated cholesterol, elevated LDL-cholesterol, elevated VLDL-cholesterol, stroke or elevated non-HDL cholesterol in the animal.
4. The method of claim 1 , wherein reducing PCSK9 expression in the animal reduces ApoB, LDL-cholesterol, VLDL-cholesterol, Lp(a), small LDL-particle, small VLDL-particle, non-HDL-cholesterol, liver triglyceride level, serum triglycerides, serum phospholipids, or any combination thereof, in the animal.
5. The method of claim 4 , wherein at least one of the ApoB reduction, LDL-cholesterol reduction, VLDL-cholesterol reduction, Lp(a) reduction, small LDL-particle reduction, small VLDL-particle reduction, non-HDL-cholesterol reduction, liver triglyceride level reduction, serum triglycerides reduction, or serum phospholipids reduction is at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100%.
6. The method of claim 1 , wherein the modified oligonucleotide has a nucleobase sequence at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1 as measured over the entirety of said modified oligonucleotide.
7. The method of claim 1 , wherein the animal is a human.
8. The method of claim 1 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
9. The method of claim 8 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.
10. The method of claim 8 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
11. The method of claim 1 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar.
12. The method of claim 11 , wherein at least one modified sugar is a bicyclic sugar.
13. The method of claim 11 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a (4′-CH(CH 3 )—O-2′) BNA, a (4′ CH2-O-2′) BNA or a 4′ (CH2)n-O-2′ bridge, wherein n is 1 or 2.
14. The method of claim 1 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase.
15. The method of claim 14 , wherein the modified nucleobase is a 5-methylcytosine.
16. The method of claim 1 , wherein the modified oligonucleotide consists of 19 to 22 linked nucleosides.
17. The method of claim 1 , wherein the compound is co-administered with one or more other pharmaceutical agents.
18. The method of claim 1 , wherein the modified oligonucleotide is conjugated.
19. The method of claim 1 , wherein the modified oligonucleotide comprises an oligonucleotide consisting of 12 to 30 linked nucleosides, wherein the nucleobase sequence of the oligonucleotide is at least 90% complementary to an equal length portion of region 3472-3562 of SEQ ID NO: 1.
20. The method of claim 1 , wherein the compound is single-stranded.