Conjugated antisense compounds and their use
Provided herein are oligomeric compounds with conjugate groups. In certain embodiments, the oligomeric compounds are conjugated to N-Acetylgalactosamine.
1. A compound comprising a conjugate having the formula:
2. The compound of claim 1 , further comprising a linker joined to the conjugate.
3. The compound of claim 2 , wherein the linker comprises an amine, an amide, an ester, an ether, a pyrrolidine, PEG, a polyamide, or a disulfide bond.
4. The compound of claim 2 , wherein the linker does not comprise a pyrrolidine.
5. The compound of claim 2 , wherein the linker has the formula:
6. The compound of claim 2 , wherein the linker has the formula:
wherein:
CM is a cleavable moiety and T 3 is a nucleoside, a nucleotide, a monomeric subunit, or an oligomeric compound.
7. The compound of claim 2 , wherein the linker has the formula:
wherein:
T 3 is a nucleoside, a nucleotide, a monomeric subunit, or an oligomeric compound.
8. The compound of claim 7 , wherein T 3 is a group comprising an oligomeric compound, and wherein the oligomeric compound is a modified oligonucleotide.
9. The compound of claim 8 , wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides wherein at least one nucleoside is a modified nucleoside.
10. The compound of claim 8 , wherein the modified oligonucleotide comprises at least one modified nucleoside selected from among: a 2′-MOE nucleoside, a 2′-OMe nucleoside, a 2′-F nucleoside, a (4′-CH 2 —O-2′) bicyclic nucleoside, a (4′-(CH 2 ) 2 —O-2′) bicyclic nucleoside, a (4′-C(CH 3 )H—O-2′) bicyclic nucleoside; and a morpholino.
11. The compound of claim 8 , wherein the modified oligonucleotide has a gapmer sugar motif comprising:
a 5′-region consisting of 2-8 linked 5′-region nucleosides, wherein at least two 5′-region nucleosides are modified nucleosides and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;
a 3′-region consisting of 2-8 linked 3′-region nucleosides, wherein at least two 3′-region nucleosides are modified nucleosides and wherein the 5′-most 3′-region nucleoside is a modified nucleoside; and
a central region between the 5′-region and the 3′-region consisting of 5-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside.
12. The compound of claim 11 , wherein each 5′-region nucleoside is a modified nucleoside; each 3′-region nucleoside is a modified nucleoside; and each central region nucleoside is an unmodified deoxynucleoside.
13. The compound of claim 12 , wherein the 5′-region consists of 2-5 linked 5′-region nucleosides; the 3′-region consists of 2-5 linked 3′-region nucleosides; and the central region consists of 8-10 central region nucleosides.
14. The compound of claim 8 , wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.
15. The compound of claim 14 , wherein the modified oligonucleotide comprises at least one phosphodiester internucleoside linkage.
16. The compound of claim 15 , wherein each internucleoside linkage of the modified oligonucleotide is either phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage.
17. The compound of claim 8 , wherein the modified oligonucleotide is an antisense oligonucleotide.
18. The compound of claim 17 , wherein the modified oligonucleotide is complementary to a target nucleic acid.
19. The compound of claim 18 , wherein the modified oligonucleotide is single-stranded.
20. The compound of claim 18 , wherein the modified oligonucleotide is double-stranded.
21. The compound of claim 20 , wherein the modified oligonucleotide activates the RISC pathway.