Compositions and methods for modulating angiopoietin-like 3 expression
Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease and/or metabolic disease, or a symptom thereof, in an individual in need thereof.
1. A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 20 contiguous nucleobases complementary to an equal length portion of nucleobases 1140 to 1159 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1; and wherein the conjugate group comprises:
2. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar.
3. The compound of claim 2 , wherein at least one modified sugar is a bicyclic sugar.
4. The compound of claim 2 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH 2 ) n —O-2′ bridge, wherein n is 1 or 2.
5. The compound of claim 2 , wherein at least one modified sugar is 2′-O-methoxyethyl.
6. The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
7. The compound of claim 6 , wherein the modified nucleobase is a 5-methylcytosine.
8. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide.
9. The compound of claim 1 , wherein the conjugate group is linked to the modified oligonucleotide at the 3′ end of the modified oligonucleotide.
10. The compound of claim 1 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage.
11. The compound of claim 10 , wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages.
12. The compound of claim 10 , wherein the modified oligonucleotide comprises at least 2 phosphorothioate internucleoside linkages.
13. The compound of claim 1 , wherein the modified oligonucleotide is single stranded.
14. The compound of claim 1 , wherein the modified oligonucleotide is double stranded.
15. 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.
16. The compound of claim 15 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
17. The compound of claim 16 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
18. The compound of claim 1 , 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, and wherein each cytosine residue is a 5-methylcytosine.
19. The compound of claim 18 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage.
20. The compound of claim 19 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
21. The compound of claim 1 , wherein the modified oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 77, and 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 internucleoside linkage in the gap segment is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.
22. The compound of claim 21 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment.
23. The compound of claim 21 , wherein the internucleoside linkages are phosphorothioate linkages between nucleosides 1-2, nucleosides 6-16 and nucleosides 18-20 of the modified oligonucleotide, wherein nucleosides 1-20 are positioned 5′ to 3′.
24. The compound of claim 21 , wherein the 2 nd , 3 rd , 4 th and 5 th internucleoside linkage from the 5′-end is a phosphodiester internucleoside linkage, wherein the 3 rd and 4 th internucleoside linkage from the 3′-end is a phosphodiester internucleoside linkage, and wherein each remaining internucleoside linkage is a phosphorothioate internucleoside linkage.
25. The compound of claim 1 , having the formula:
wherein either R 1 is —OCH 2 CH 2 OCH 3 (MOE) and R 2 is H; or R 1 and R 2 together form a bridge, wherein R 1 is —O— and R 2 is —CH 2 —, —CH(CH 3 )—, or —CH 2 CH 2 —, and R 1 and R 2 are directly connected such that the resulting bridge is selected from: —O—CH 2 —, —O—CH(CH 3 )—, and —O—CH 2 CH 2 —;
and for each pair of R 3 and R 4 on the same ring, independently for each ring: either R 3 is selected from H and —OCH 2 CH 2 OCH 3 and R 4 is H; or R 3 and R 4 together form a bridge, wherein R 3 is —O—, and R 4 is —CH 2 —, —CH(CH 3 )—, or —CH 2 CH 2 — and R 3 and R 4 are directly connected such that the resulting bridge is selected from: —O—CH 2 —, —O—CH(CH 3 )—, and —O—CH 2 CH 2 —;
and R 5 is selected from H and —CH 3 ;
and Z is selected from S − and O − .
26. The compound of claim 1 , having the formula:
27. A composition comprising the compound of claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent.
28. A composition comprising the compound of claim 26 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent.