Antisense oligomers targeting PCSK9
View Patent ↗The present invention relates to oligomer compounds (oligomers), which target PCSK9 mRNA in a cell, leading to reduced expression of PCSK9. Reduction of PCSK9 expression is beneficial for the treatment of certain medical disorders, such as hypercholesterolemia and related disorders.
1. A single stranded oligomer of between 10-18 nucleotides in length which comprises a contiguous nucleotide sequence selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 21, or a contiguous nucleotide sequence with no more than one or two mismatches when compared to SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 21, wherein the oligomer is capable of recruiting RNase H when formed in a duplex with a complementary target RNA, and wherein the contiguous nucleotide sequence comprises one or more nucleotide analogues.
2. The oligomer according to claim 1 , wherein the contiguous nucleotide sequence is selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, and SEQ ID NO: 21.
3. The oligomer according to claim 1 , wherein the nucleotide sequence of the oligomer consists of the contiguous nucleotide sequence.
4. The oligomer according to claim 1 , wherein the contiguous nucleotide sequence is between 12-16 nucleotides in length.
5. The oligomer according to claim 1 , wherein the one or more nucleotide analogues are sugar modified nucleotides selected from the group consisting of: Locked Nucleic Acid (LNA) units, 2′-O-alkyl-RNA units, 2′-OMe-RNA units, 2′MOE units, 2′-amino-DNA units, and 2′-fluoro-DNA units.
6. The oligomer according to claim 5 , wherein the one or more nucleotide analogues are LNA.
7. The oligomer according to claim 1 which is a gapmer selected from the group consisting of SEQ ID NO 11, SEQ ID NO: 12, SEQ ID NO: 14, and SEQ ID NO: 15.
8. The oligomer according to claim 7 , wherein the oligomer is a LNA gapmer selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 20.
9. The oligomer according to claim 1 , which inhibits the expression of PCSK9 gene or mRNA in a cell which is expressing PCSK9 gene or mRNA.
10. The oligomer according to claim 8 , wherein the oligomer consists of or comprises any one of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 4, and SEQ ID NO: 10.
11. A conjugate comprising the oligomer according to claim 1 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said oligomer.
12. A pharmaceutical composition comprising the oligomer according to claim 1 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
13. The oligomer according to claim 1 , which treats or prevents hypercholesterolemia and related disorders.
14. A method of treating hypercholesterolemia and related disorders, said method comprising administering an effective amount of the oligomer according to claim 1 , to a patient suffering from, or likely to suffer from hypercholesterolemia and related disorders.
15. A method for the inhibition of PCSK9 in a cell which is expressing PCSK9, said method comprising administering the oligomer according to claim 1 to said cell so as to inhibit PCSK9 in said cell.
16. A pharmaceutical composition comprising the conjugate according to claim 11 , and a pharmaceutically acceptable diluent, carrier, salt or adjuvant.
17. The oligomer according to claim 1 , wherein said contiguous nucleotide sequence is connected by an internucleotide linkage selected from the group consisting of phosphodiester, phosphorothioate, and boranophosphate.
18. The oligomer according to claim 1 , wherein said contiguous nucleotide sequence comprises at least one nucleobase selected from the group consisting of xanthine, hypoxanthine, 5-methylcytosine, isocytosine, pseudoisocytosine, 5-bromouracil, 5-propynuluracil, 6-aminopurine, 2-aminopurine, inosine, diaminopurine, and 2-chloro-6-aminopurine.
19. A method of increasing LDL receptor protein level in a cell comprising administering an effective amount of the oligomer according to claim 1 to said cell, wherein said oligomer inhibits PCSK9 mRNA level, thereby increasing LDL receptor protein expression.
20. A method of reducing cholesterol within a cell comprising administering an effective amount of the oligomer according to claim 1 to said cell, wherein said oligomer inhibits PCSK9 mRNA, thereby lowering cholesterol level.
21. The method of claim 14 , wherein said disorder is selected from the group consisting of atherosclerosis, hyperlipidemia, HDL or LDL cholesterol imbalance, dyslipidemias, familial combined hyberlipidemia (FCHL), acquired hyperlipidemia, statin-resistant hypercholesterolemia, coronary artery disease (CAD), and coronary heart disease (CHD).
22. A method of detecting or quantitating PCSK9 mRNA level in a cell, comprising adding the oligomer of claim 1 and measuring the oligomer level bound to the PCSK9 mRNA in the cell.