RNA antagonist compounds for the inhibition of Apo-B100 expression

1. An oligomeric compound 12, 13, or 14 nucleobases in length, wherein the nucleobase sequence of the compound is selected from the group consisting of SEQ ID NO:5, 9 and 13, and wherein said compound comprises at least 2 nucleotide analogues.

2. The compound according to claim 1 , wherein the nucleobase sequence comprises, in a 5′ to 3′ direction, i) region A: a stretch of 2-4 nucleotide analogues, followed by ii) region B: a stretch of 6-11 nucleotides, which is followed by iii) region C: a stretch of 2-4 nucleotide analogues.

3. The compound according to claim 1 , wherein the internucleobase linkage groups between the nucleobase units of the nucleobase sequence are independently selected from either phosphorothioate or phosphodiester linkage groups.

4. The compound of claim 1 , wherein the nucleotide analogues are independently selected from the group consisting of: 2′-O-alkyl-RNA monomers, 2′-amino-DNA monomers, 2′-fluoro-DNA monomers, locked nucleic acid (LNA) monomers, arabino nucleic acid (ANA) monomers, 2′-fluoro-ANA monomers, D-hexitol nucleic acid (HNA) monomers, and intercalating nucleic acid (INA) monomers.

5. The compound according to claim 4 wherein at least one of said nucleotide analogues is a locked nucleic acid (LNA).

6. The compound according to claim 5 wherein all the nucleotide analogues are LNA.

7. The compound according to claim 5 , wherein the LNA is selected from the group consisting of: beta-D-oxy-LNA, alpha-L-oxy-LNA, beta-D-amino-LNA and beta-D-thio-LNA.

8. The compound according to claim 1 , which is selected from the group consisting of:

5′-A s G s Me C s a s t s t s g s g s t s a s t s T s Me C s A s G-3′ (SEQ ID NO:17);

5′-AG s Me C s a s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:18);

5′-A s G Me C s a s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:19);

5′-A s G s Me Ca s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:20);

5′-A s G s Me C s a s t s t s g s g s t s a s tT s Me C s A-3′ (SEQ ID NO:21);

5′-A s G s Me C s a s t s t s g s g s t s a s t s T Me C s A-3′ (SEQ ID NO:22);

5′-A s G s Me C s a s t s t s g s g s t s a s t s T s Me CA-3′ (SEQ ID NO:23);

5′-AG s Me C s a s t s t s g s g s t s a s t s T s Me CA-3′ (SEQ ID NO:24);

5′-AG Me C s a s t s t s g s g s t s a s t s T Me CA-3′ (SEQ ID NO:25);

5′-G s Me C s a s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:26);

5′-G Me C s a s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:27);

5′-G s Me Ca s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:28);

5′-G s Me C s a s t s t s g s g s t s a s tT s Me C s A-3′ (SEQ ID NO:29);

5′-G s Me C s a s t s t s g s g s t s a s t s T Me C s A-3′ (SEQ ID NO:30);

5′-G s Me C s a s t s t s g s g s t s a s t s T s Me CA-3′ (SEQ ID NO:31);

5′-G Me C s a s t s t s g s g s t s a s t s T s Me CA-3′ (SEQ ID NO:32);

5′-G Me C s a s t s t s g s g s t s a s t s T Me CA-3′ (SEQ ID NO:33);

5′-G s Me C s a s t s t s g s g s t s a s t s T s Me C-3′ (SEQ ID NO:34);

5′-G Me C s a s t s t s g s g s t s a s t s T s Me C-3′ (SEQ ID NO:35);

5′-G s Me Ca s t s t s g s g s t s a s t s T s Me C-3′ (SEQ ID NO:36);

5′-G s Me C s a s t s t s g s g s t s a s tT s Me C-3′ (SEQ ID NO:37);

5′-G s Me C s a s t s t s g s g s t s a s t s T Me C-3′ (SEQ ID NO:38);

5′-G Me C s a s t s t s g s g s t s a s t s T Me C-3′ (SEQ ID NO:39); and

5′-G Me Ca s t s t s g s g s t s a s tT Me C-3′ (SEQ ID NO:40), wherein the capital letters represent locked nucleic acid (LNA) monomers, lowercase letters represent DNA monomers, internucleoside linkages are phosphorthioate where indicated by the subscript s or phosphodiester as indicated by the lack of the subscript s, and superscript Me indicates that LNA C have a 5-methyl group.

9. The compound of claim 1 wherein all of the nucleotide analogues are locked nucleic acids (LNA).

10. The compound of claim 9 wherein all of the internucleobase linkage groups between the nucleobase units of the nucleobase sequence are phosphorothioate linkage groups.

11. A conjugate comprising the compound according to any of claims 1 , 2 , 3 , 7 , 8 , 9 and 10 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to said compound.

12. A pharmaceutical composition comprising the compound according to any of claims 1 , 2 , 5 , 3 , 8 , 9 and 10 and a pharmaceutically acceptable diluent, carrier or adjuvant.

13. A method of treating a disease or condition characterized by abnormal levels of apolipoprotein B100 (Apo-B100) comprising administering to a subject in need thereof an effective amount of the compound according to any of claims 1 , 2 , 3 , 7 , 8 , 9 and 10 .

14. The method of claim 13 , wherein the disease or condition is selected from the group consisting of: atherosclerosis, hypercholesterolemia and hyperlipidemia.

15. The compound of claim 1 , wherein said compound comprises at least 3 nucleotide analogues.

16. The compound of claim 2 , wherein the nucleotides in region B are DNA nucleotides.

17. The compound of claim 2 , further comprising one or two nucleotides (region D), wherein the nucleobase sequence comprises, in a 5′ to 3′ direction: region D, followed by region A, followed by region B, followed by region C.

18. A pharmaceutical composition comprising the conjugate of claim 11 , and a pharmaceutically acceptable diluent, carrier, or adjuvant.

19. A method of treating a disease or condition characterized by abnormal levels of apolipoprotein B100 (Apo-B100) comprising administering to a subject an effective amount of the conjugate of claim 11 .

20. The method of claim 19 , wherein the disease or condition is selected from the group consisting of: atherosclerosis, hypercholesterolemia, and hyperlipidemia.

21. The oligomeric compound 5′-G s Me C s a s a s t s t s g s g s t s a s t s T s Me C s A-3′ (SEQ ID NO:26), wherein the capital letters represent beta-D-oxy-LNA monomers, lowercase letters represent DNA monomers, all internucleoside linkages are phosphorthioate, as indicated by the subscript s, and superscript Me indicates that the beta-D-oxy-LNA C have a 5-methyl group.

22. A conjugate comprising the compound according to claim 21 and at least one non-nucleotide or non-polynucleotide moiety covalently attached to the compound.

23. A pharmaceutical composition comprising the compound according to claim 21 and a pharmaceutically acceptable diluent, carrier or adjuvant.

24. A pharmaceutical composition comprising the conjugate according to claim 22 and a pharmaceutically acceptable diluent, carrier or adjuvant.

25. A method of treating a disease or condition characterized by abnormal levels of apolipoprotein B100 (Apo-B100) comprising administering to a subject in need thereof an effective amount of the compound according to claim 21 .

26. The method of claim 25 , wherein the disease or condition is selected from the group consisting of: atherosclerosis, hypercholesterolemia and hyperlipidemia.

27. A method of treating a disease or condition characterized by abnormal levels of apolipoprotein B100 (Apo-B100) comprising administering to a subject in need thereof an effective amount of the conjugate according to claim 22 .

28. The method of claim 27 , wherein the disease or condition is selected from the group consisting of: atherosclerosis, hypercholesterolemia and hyperlipidemia.