Modulation of apolipoprotein c-III expression
View Patent ↗Compounds, compositions and methods are provided for modulating the expression of apolipoprotein C-III. The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein C-III. Methods of using these compounds for modulation of apolipoprotein C-III expression and for diagnosis and treatment of disease associated with expression of apolipoprotein C-III are provided.
1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides comprising an at least 8 consecutive nucleobase portion complementary to an equal number of nucleobases of nucleotides 3533-3552 of SEQ ID NO: 4, wherein said modified oligonucleotide is at least 90% complementary to SEQ ID NO: 4.
2. The compound of claim 1 , consisting of a single-stranded modified oligonucleotide.
3. The compound of claim 1 , wherein said modified oligonucleotide is at least 95% complementary to SEQ ID NO: 4.
4. The compound of claim 1 , wherein said modified oligonucleotide is 100% complementary to SEQ ID NO: 4.
5. The compound of claim 2 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.
6. The compound of claim 5 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
7. The compound of claim 2 , wherein at least one nucleoside comprises a modified sugar.
8. The compound of claim 7 , wherein at least one modified sugar is a bicyclic sugar.
9. The compound of claim 7 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl.
10. The compound of claim 1 , wherein the modified oligonucleotide comprises:
a gap segment consisting of linked deoxynucleosides;
a 5′ wing segment consisting of linked nucleosides;
a 3′ wing segment consisting of linked nucleosides;
wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.
11. The compound of claim 10 , wherein the modified oligonucleotide comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting 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; wherein each cytosine residue of the modified oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.
12. The compound of claim 11 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
13. The compound of claim 12 , wherein the 20 linked nucleosides are complementary to nucleotides 3533-3552 of SEQ ID NO: 4.
14. The compound of claim 1 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 87.
15. The compound of claim 1 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 87 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting 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, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.
16. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
17. The composition of claim 16 , wherein said modified oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 87 and comprises:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting 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, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.
18. A modified oligonucleotide consisting of 20 linked nucleosides comprising the nucleobase sequence of SEQ ID NO: 87 and:
a gap segment consisting of ten linked deoxynucleosides;
a 5′ wing segment consisting of five linked nucleosides;
a 3′ wing segment consisting 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, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage, and wherein each cytosine residue of said modified oligonucleotide is a 5-methylcytosine.