Antisense oligomers targeting PCSK9
The present invention relates to oligomeric compounds and conjugates thereof that target Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for a range of medical disorders, such as hypercholesterolemia and related disorders.
1. A compound consisting of an antisense oligomer that is 16 contiguous nucleotides in length, wherein the sequence of the antisense oligomer is 100% complementary to the sequence of SEQ ID NO: 31, wherein the antisense oligomer is a gapmer comprising at least one LNA unit, and wherein the antisense oligomer targets mRNA encoding PCSK9.
2. The compound of claim 1 , wherein the LNA is oxy-LNA, thio-LNA, amino-5 LNA, 5′-methyl-LNA, ENA, cET, cMOE or a combination thereof.
3. The compound of claim 1 , wherein the LNA is in the beta-D-configuration or the alpha-L configuration.
4. The compound of claim 1 , wherein the compound and an oligomer of SEQ ID NO:31 can form a duplex with increased thermal stability with respect to a corresponding duplex comprising the corresponding antisense oligomer without LNA.
5. The compound of claim 1 , wherein the sequence of the antisense oligomer comprises at least one phosphorothioate internucleoside linkage.
6. The compound of claim 1 , wherein the sequence of the antisense oligomer is SEQ ID NO: 26.
7. The compound of claim 1 , wherein the sequence of the antisense oligomer is SEQ ID NO: 2 or SEQ ID NO: 3.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
9. A method of treating hypercholesterolemia or a related disorder selected from the group consisting of atherosclerosis, hyperlipidemia, HDL/LDL cholesterol imbalance, dyslipidemias, coronary artery disease (CAD), or coronary heart disease (CHD) in a subject in need thereof, the method comprising administering an effective amount of a compound of claim 1 to the subject, wherein the levels and/or activity of PCSK9 or expression of mutant forms of PCSK9 in the subject increases LDL cholesterol levels in the subject, and wherein the targeting of mRNA encoding PCSK9 by the compound of claim 1 reduces LDL cholesterol levels in the subject.
10. A method of reducing expression levels and/or activity of PCSK9 in a subject in need thereof comprising administering an effective amount of a compound of claim 1 to the subject.