Details for Patent: 8,735,364

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)
Assignee:	Genzyme Corporation (Cambridge, MA)
Filing Date:	Jan 03, 2008
Application Number:	11/969,096
Claims:	1. An antisense compound, or a salt form thereof, 12 to 30 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein B wherein said antisense compound comprises at least 8 consecutive nucleobases selected from the group consisting of SEQ ID NOS: 56, 68, and 69, wherein said antisense compound comprises one or more modifications selected from the group consisting of: a modified sugar moiety, a modified internucleoside linkage, and a modified nucleobase. 2. The antisense compound of claim 1, wherein said antisense compound is 20 to 30 nucleobases in length. 3. The antisense compound of claim 1, wherein said antisense compound is 20 nucleobases in length. 4. The antisense compound of claim 2, wherein said modifications comprise a modified sugar moiety selected from the group consisting of: a 2'-O-methoxyethyl modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 5. The antisense compound of claim 4, wherein the modified sugar moiety is a 2'-Omethoxyethyl sugar moiety. 6. The antisense compound of claim 4, wherein the modified sugar moiety is a bicyclic sugar moiety. 7. The antisense compound of claim 1, wherein the antisense compound is a chimeric oligonucleotide having a plurality of 2'-deoxynucleotides flanked on each side by at least one nucleotide having a modified sugar moiety. 8. The antisense compound of claim 7, wherein the modified sugar moiety is a 2'-O-methoxyethyl sugar moiety. 9. The antisense compound of claim 7, wherein the modified sugar moiety is a bicyclic sugar moiety. 10. The antisense compound of claim 9, wherein the bicyclic sugar moiety has a (--CH.sub.2--).sub.n group forming a bridge between the 2' oxygen ant the 4' carbon atoms of the sugar ring, wherein n is 1 or 2. 11. The antisense compound of claim 2, wherein the antisense compound comprises at least one modified nucleobase. 12. The antisense compound of claim 9, wherein the modified nucleobase is a 5-methylcytosine. 13. The antisense compound of claim 1, wherein the antisense oligonucleotide is a salt form. 14. The antisense compound of claim 13, wherein the salt form is a sodium salt form. 15. The antisense compound of claim 2, wherein said modifications comprise a modified internucleoside linkage. 16. The antisense compound of claim 15 wherein said modified internucleoside linkage is a phosphorothioate internucleoside linkage. 17. The antisense compound of claim 1, wherein said antisense compound is a gapmer comprising a gap segment comprised of linked 2'-deoxynucleotides positioned between 5' and 3' wing segments. 18. The antisense compound of claim 17, wherein said wing segments comprise at least one modified sugar moiety selected from the group consisting of a 2'-O-methoxyethyl modified sugar moiety, a 2'-methoxy modified sugar moiety, a 2'-O-alkyl modified sugar moiety, and a bicyclic sugar moiety. 19. The antisense compound of claim 18, wherein the modified sugar moiety is a 2'-O-methoxyethyl sugar moiety. 20. The antisense compound of claim 18, wherein the modified sugar moiety is a bicyclic sugar moiety. 21. The antisense compound of claim 17, wherein said gap segment is ten 2'-deoxynucleotides in length and each of said wing segments is five 2'-O-methoxyethyl nucleotides in length. 22. The antisense compound of claim 17, wherein the antisense oligonucleotide comprises at least one modified nucleobase. 23. The antisense compound of claim 17, wherein the modified nucleobase is a 5-methylcytosine. 24. The antisense compound of claim 17, wherein the antisense oligonucleotide is a salt form. 25. The antisense compound of claim 17, wherein the salt form is a sodium salt form. 26. The antisense compound of claim 1, wherein the antisense compound is an antisense oligonucleotide. 27. A composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier, excipient or diluent. 28. The composition of claim 27, further comprising a penetration enhancer. 29. The composition of claim 28, wherein the penetration enhancer is capric acid or lauric acid. 30. The composition of claim 27, further comprising at least one additional pharmaceutically active material. 31. The composition of claim 30, wherein the at least one additional pharmaceutically active material is an anti-inflammatory agent. 32. The antisense compound of claim 1, having i. a gap segment of ten linked 2'-deoxynucleosides, ii. a 5' wing segment of five linked nucleosides, and iii. a 3' wing segment of five linked nucleosides, wherein the gap segment is positioned between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-O-methoxyethyl sugar modification, and wherein each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein each cytidine is a 5-methylcytidine. 33. The antisense compound of claim 1, wherein said antisense compound comprises at least 8 consecutive nucleobases selected from SEQ ID NO:56. 34. The antisense compound of claim 1, wherein said antisense compound comprises at least 8 consecutive nucleobases selected from SEQ ID NO:68. 35. The antisense compound of claim 1, wherein said antisense compound comprises at least 8 consecutive nucleobases selected from SEQ ID NO:69. 36. The antisense compound of claim 1, wherein said antisense compound comprises 20 consecutive nucleobases selected from SEQ ID NO:56. 37. The antisense compound of claim 1, wherein said antisense compound comprises 20 consecutive nucleobases selected from SEQ ID NO:68. 38. The antisense compound of claim 1, wherein said antisense compound comprises 20 consecutive nucleobases selected from SEQ ID NO:69.