Linkage modified oligomeric compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11629348-B2
Application number	US-202217671924-A
Country	US
Kind code	B2
Filing date	Feb 15, 2022
Priority date	Aug 15, 2019
Publication date	Apr 18, 2023
Grant date	Apr 18, 2023

Abstract

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.

First claim

What is claimed:

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.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Anderson Brooke A
• Liang xue-hai
• Drury Iii William John
• Oestergaard Michael
• Migawa Michael T
• Seth Punit P

Classifications

• C12N2310/314

  Phosphoramidates · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2310/323

  modified ring structure · CPC title

• C12N2310/341

  Gapmers, i.e. of the type ===---=== · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title