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Details for Patent: 7,803,930

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Details for Patent: 7,803,930

Title:Antisense modulation of apolipoprotein B-expression
Abstract: Antisense compounds, compositions and methods are provided for modulating the expression of apolipoprotein B. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding apolipoprotein B. Methods of using these compounds for modulation of apolipoprotein B expression and for treatment of diseases associated with expression of apolipoprotein B are provided.
Inventor(s): Crooke; Rosanne M. (Carlsbad, CA), Graham; Mark J. (San Clemente, CA), Freier; Susan M. (San Diego, CA)
Assignee: Isis Pharmaceuticals, Inc. (Carlsbad, CA)
Filing Date:Aug 17, 2004
Application Number:10/920,612
Claims:1. An antisense compound 12 to 30 nucleobases in length, wherein said antisense compound is fully complementary within the range of nucleotides 5562-5625 of SEQ ID NO:3, and comprises at least one modified sugar moiety.

2. The antisense compound of claim 1, wherein said antisense compound is fully complementary within the range of nucleotides 5582-5625 of SEQ ID NO:3.

3. The antisense compound of claim 1, wherein said antisense compound is targeted to the range of nucleotides 5589-5608 of SEQ ID NO:3 and is fully complementary over its length to SEQ ID NO: 3.

4. The antisense compound of claim 1, wherein said antisense compound comprises at least 8 contiguous nucleobases of SEQ ID NO: 224.

5. The antisense compound of claim 1, wherein said antisense compound comprises SEQ ID NO: 224.

6. The antisense compound of claim 1, wherein the antisense compound comprises an antisense oligonucleotide.

7. The antisense compound of claim 1, wherein the antisense compound further comprises one or more modifications selected from the group consisting of a modified backbone and a modified nucleobase.

8. The antisense compound of claim 1, wherein the modified sugar moiety is selected from the group consisting of a 2'-methoxyethoxy modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, and a bicyclic nucleic acid sugar moiety.

9. The antisense compound of claim 1, wherein the antisense compound is single-stranded.

10. The antisense compound of claim 1, wherein the antisense compound is double-stranded.

11. A composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

12. The antisense compound of claim 1, wherein the antisense compound is covalently linked to a lipid moiety.

13. The antisense compound of claim 12 wherein the lipid moiety comprises a cholesterol.

14. The antisense compound of claim 1, wherein the antisense compound is 20 to 30 nucleobases in length.

15. The antisense compound of claim 1, wherein the antisense compound is 20 nucleobases in length.

16. The antisense compound of claim 1, wherein the antisense compound is a chimeric antisense compound.

17. An antisense compound 20 to 30 nucleobases in length comprising at least 13 contiguous nucleobases of SEQ ID NO: 224 and at least one modified sugar moiety, wherein said antisense compound specifically hybridizes to SEQ ID NO:3.

18. The antisense compound of claim 17, wherein the antisense compound is 20 nucleobases in length.

19. The antisense compound of claim 17, wherein the modified sugar moiety is a 2'-methoxyethoxy modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, or a bicyclic nucleic acid sugar moiety.

20. The antisense compound of claim 17, wherein the antisense compound is an antisense oligonucleotide.

21. The antisense compound of claim 20, wherein the antisense oligonucleotide is a chimeric antisense oligonucleotide.

22. The antisense compound of claim 21, wherein the chimeric antisense oligonucleotide comprises a gap segment of 2'-deoxynucleotides positioned between wing segments, wherein each nucleotide of each wing segment comprises a 2'-methoxyethoxy sugar moiety.

23. The antisense compound of claim 22, wherein the gap segment is ten 2'-deoxynucleotides in length and each wing segment comprises from one to nine 2'-methoxyethyoxy nucleotides.

24. The antisense compound of claim 22, wherein the gap segment is ten 2'-deoxynucleotides and each wing segment comprises five 2'-methoxyethoxy nucleotides.

25. The antisense compound of claim 17, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

26. The antisense compound of claim 17, wherein each cytosine is a 5-methylcytosine.

27. The antisense compound of claim 17, wherein the antisense compound is covalently linked to a lipid moiety.

28. The antisense compound of claim 27, wherein the lipid moiety is cholesterol.

29. The antisense compound of claim 17, wherein the antisense compound is fully complementary to SEQ ID NO: 3.

30. The antisense compound of claim 17, wherein the antisense compound comprises SEQ ID NO: 224.

31. The antisense compound of claim 17, wherein the antisense compound consists of SEQ ID NO: 224.

32. An antisense oligonucleotide consisting of SEQ ID NO: 224, wherein nucleobases 1-5 and 16-20 comprise 2'-methoxyethoxy nucleotides, nucleobases 6-15 are 2'-deoxynucleotides, each internucleoside linkage is a phosphorothioate internucleoside linkage, and each cytosine is a 5-methylcytosine.

33. The antisense oligonucleotide of claim 32, wherein the antisense oligonucleotide is in a salt form.

34. The antisense oligonucleotide of claim 33, wherein the salt is sodium salt.

35. A composition comprising the antisense oligonucleotide of any of claims 17, 32, 33 or 34 and a pharmaceutically acceptable carrier or diluent.

36. The antisense compound of claim 17, wherein said antisense compound inhibits expression of apolipoprotein B mRNA in HepG2 cells by at least 40% when contacted with the HepG2 cells at a concentration of 50 nM.
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