Compositions and methods for modulating apolipoprotein (a) expression
View Patent ↗Provided herein are oligomeric compounds with conjugate groups targeting apoplipoprotein (a) [apo(a)]. In certain embodiments, the apo(a) targeting oligomeric compounds are conjugated to N-Acetylgalactosamine. Also disclosed herein are conjugated oligomeric compounds targeting apo(a) for use in decreasing apo(a) to treat, prevent, or ameliorate diseases, disorders or conditions related to apo(a) and/or Lp(a). Certain diseases, disorders or conditions related to apo(a) and/or Lp(a) include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The conjugated oligomeric compounds disclosed herein can be used to treat such diseases, disorders or conditions 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 3901 to 3920 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 at least one nucleoside comprises a 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: 58, 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: