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|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:||Aug 01, 2001|
|Claims:||1. An oligonucleotide 12 to 30 nucleobases in length, or a salt thereof, targeted to a nucleic acid molecule encoding apolipoprotein B, wherein the oligonucleotide is 100% complementary to SEQ ID NO: 3 and wherein the oligonucleotide comprises at least 8 consecutive nucleobases of SEQ ID NO:27. |
2. The oligonucleotide of claim 1 comprising at least one modified nucleobase.
3. The oligonucleotide of claim 2 wherein the modified nucleobase is a 5-methylcytosine.
4. The oligonucleotide of claim 1 wherein the oligonucleotide is a chimeric oligonucleotide.
5. The oligonucleotide of claim 1, wherein the oligonucleotide inhibits the expression of the long form of apolipoprotein B, ApoB-100.
6. The oligonucleotide of claim 1, wherein the oligonucleotide comprises a modified sugar moiety.
7. The oligonucleotide of claim 6, wherein the modified sugar moiety is a 2' substituted sugar moiety or a bicyclic sugar moiety.
8. The oligonucleotide of claim 7, wherein the 2' substituted sugar moiety is a 2'-O-methoxyethyl sugar moiety.
9. The oligonucleotide of claim 7, wherein the bicyclic sugar moiety is a locked nucleic acid.
10. The oligonucleotide of claim 7, wherein the bicyclic sugar moiety has a (--CH.sub.2--).sub.n group forming a bridge between the 2' oxygen and the 4' carbon atoms of the sugar ring, wherein n is 1 or 2.
11. The oligonucleotide of claim 1, wherein the oligonucleotide comprises at least one modified internucleoside linkage.
12. The oligonucleotide of claim 11, wherein the modified internucleoside linkage is a phosphorothioate linkage.
13. The oligonucleotide 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.
14. The oligonucleotide of claim 13, the oligonucleotide comprising at least one cytosine, wherein each cytosine is a 5-methylcytosine.
15. The oligonucleotide of claim 1, wherein the oligonucleotide comprises 20 nucleobases.
16. The oligonucleotide of claim 15, wherein the oligonucleotide consists of 20 nucleobases.
17. The oligonucleotide of claim 1, wherein the oligonucleotide is an oligonucleotide salt.
18. The oligonucleotide of claim 15, wherein the salt is a sodium salt.
19. A composition comprising the oligonucleotide of claim 1 and a pharmaceutically acceptable carrier or diluent.
20. The composition of claim 19 further comprising a colloidal dispersion system.
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