Linkage modified oligomeric compounds and uses thereof
The present disclosure provides oligomeric compounds (including oligomeric compounds that are antisense agents or portions thereof) comprising a modified oligonucleotide having at least one modified internucleoside linking group.
1. An oligomeric compound comprising a modified oligonucleotide consisting of 12-22 linked nucleosides, wherein the modified oligonucleotide has a 5′-region, a central region, and a 3′-region, wherein:
the 5′-region consists of 1-6 linked nucleosides, each comprising a modified sugar moiety;
the 3′-region consists of 1-6 linked nucleosides, each comprising a modified sugar moiety;
the central region is a deoxy region; and
the central region consists of 7-12 linked nucleosides and has the formula (from 5′ to 3′): (N d1 ) L1 (N d2 ) L2 (N d3 ) L3 (N d4 ) L4 [(N d ) L5 ] q , wherein:
N d1 , N d2 , N d3 , N d4 are independently selected from a stereo-standard DNA nucleoside and a 2′-substituted nucleoside; with the proviso that no more than one of N d1 , N d2 , N d3 , or N d4 is a 2′-substituted nucleoside;
q is from 3-8;
each of L 1 , L 2 , L 3 , L 4 , and each L 5 is an internucleoside linkage:
two, three, or four of L 1 , L 2 , L 3 , and L 4 are mesyl phosphoramidate internucleoside linkages; and
each L 5 is a phosphorothioate internucleoside linkage.
2. The oligomeric compound of claim 1 , wherein each internucleoside linkage of the 3′-region and each internucleoside linkage of the 5′-region of the modified oligonucleotide is independently selected from a phosphorothioate and a phosphodiester.
3. The oligomeric compound of claim 1 , wherein each nucleoside of the deoxy region is a stereo-standard DNA nucleoside.
4. The oligomeric compound of claim 1 , wherein exactly one nucleoside of the deoxy region is a 2′-substituted nucleoside, and the remainder of the nucleosides of the deoxy region are stereo-standard DNA nucleosides.
5. The oligomeric compound of claim 4 , wherein the 2′-substituted nucleoside comprises a stereo-standard 2′-OMe sugar moiety.
6. The oligomeric compound of claim 1 , wherein each modified sugar moiety is independently selected from a bicyclic sugar moiety and a 2′-substituted sugar moiety.
7. The oligomeric compound of claim 6 , wherein each bicyclic sugar moiety is independently selected from cEt, LNA, and ENA.
8. The oligomeric compound of claim 6 , wherein each 2′-substituted sugar moiety is independently selected from 2′-OMe and 2′-MOE.
9. The oligomeric compound of claim 8 , wherein each 2′-substituted sugar moiety is a stereo-standard sugar moiety.
10. The oligomeric compound of claim 1 , wherein L 1 and L 2 are mesyl phosphoramidate internucleoside linkages.
11. The oligomeric compound of claim 1 , wherein L 2 and L 3 are mesyl phosphoramidate internucleoside linkages.
12. The oligomeric compound of claim 1 , wherein L 3 and L 4 are mesyl phosphoramidate internucleoside linkages.
13. The oligomeric compound of claim 1 , wherein L 1 , L 2 , and L 3 are mesyl phosphoramidate internucleoside linkages.
14. The oligomeric compound of claim 1 , wherein L 2 , L 3 , and L 4 are mesyl phosphoramidate internucleoside linkages.
15. The oligomeric compound of claim 1 , wherein L 1 , L 2 , L 3 , and L 4 are mesyl phosphoramidate internucleoside linkages.
16. The oligomeric compound of claim 1 , wherein each of L 1 , L 2 , L 3 , L 4 are independently selected from a mesyl phosphoramidate and a phosphorothioate internucleoside linkage, and each L 5 is a phosphorothioate internucleoside linkage.
17. The oligomeric compound of claim 4 , wherein N d2 is a stereo-standard 2′-OMe nucleoside.
18. The oligomeric compound of claim 1 , wherein
the 5′-region consists of 3 linked nucleosides, each comprising a bicyclic sugar moiety;
the 3′ region consists of 3 linked nucleosides, each comprising bicyclic sugar moiety;
and the central region consists of 10 linked nucleosides.
19. The oligomeric compound of claim 18 , wherein each bicyclic sugar moiety is a cEt sugar moiety.
20. The oligomeric compound of claim 1 , wherein
the 5′-region consists of 5 linked nucleosides, each comprising a stereo-standard 2′-MOE sugar moiety;
the 3′ region consists of 5 linked nucleosides, each comprising a stereo-standard 2′-MOE sugar moiety; and the central region consists of 10 linked nucleosides.
21. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 16-20, 16-18, 18-20, or 18-22 linked nucleosides.
22. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 16 linked nucleosides.
23. The oligomeric compound of claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
24. The oligomeric compound of claim 1 , wherein the oligomeric compound comprises a conjugate group.
25. The oligomeric compound of claim 24 , wherein the conjugate group comprises a conjugate linker and a conjugate moiety.
26. The oligomeric compound of claim 25 , wherein the conjugate moiety is selected from a cell-targeting moiety, a lipid, a carbohydrate, a C 12 -C 20 alkyl, an antibody, an antibody fragment, or a peptide.
27. The oligomeric compound of claim 26 , wherein the conjugate moiety comprises a GalNAc.
28. The oligomeric compound of claim 1 , wherein each nucleobase of the modified oligonucleotide is independently selected from thymine, uracil, guanine, cytosine, 5-methylcytosine, and adenine.