Conjugated antisense compounds and their use

Patent metadata

Field	Value
Publication number	US-11725208-B2
Application number	US-201816771620-A
Country	US
Kind code	B2
Filing date	Dec 14, 2018
Priority date	Dec 14, 2017
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

Abstract

The present disclosure provides half duplex compounds comprising a first oligomeric compound and a second, shorter, oligomeric compound, wherein the first oligomeric compound is complementary to a target nucleic acid and the second oligomeric compound is complementary to the first oligomeric compound. In certain embodiments, the compounds disclosed herein are useful for modulating the expression of extra-hepatic target nucleic acids.

First claim

The invention claimed is:

1. A compound comprising a first oligomeric compound and a second oligomeric compound, wherein the first oligomeric compound comprises a first modified oligonucleotide consisting of 14-20 linked nucleosides and has a nucleobase sequence complementary to the nucleobase sequence of the second oligomeric compound and to a nucleic acid target; and
the second oligomeric compound comprises a second modified oligonucleotide consisting of 6-12 linked nucleosides;
wherein the first modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 1-5 linked 5′-nucleosides,
a central region consisting of 6-10 linked central region nucleosides, and
a 3′-region consisting of 1-5 linked 3′-nucleosides; wherein

each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety; and
wherein the second modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 2-4 linked 5′-nucleosides,
a central region consisting of 2-4 linked central region nucleosides, and
a 3′-region consisting of 2-4 linked 3′-nucleosides; wherein

each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.

2. The compound of claim 1 , wherein the first modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 90%, or 100% complementary to the nucleobase sequence of the target nucleic acid, when measured across the entire nucleobase sequence of the first modified oligonucleotide.

3. The compound of claim 1 , wherein the first modified oligonucleotide comprises at least 5, at least 6, at least 7, or at least 8 contiguous linked 2′-deoxynucleosides.

4. The compound of claim 1 , wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.

5. The compound of claim 1 , wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety selected from cEt and LNA.

6. The compound of claim 1 , wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety comprising a 2′-MOE or 2′-OMe.

7. The compound of claim 1 , wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate selected from a morpholino, a PNA, a F-HNA, a THP, or a modified THP.

8. The compound of claim 1 , wherein the first modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 5 linked 5′-nucleosides,
a central region consisting of 10 linked central region nucleosides, and
a 3′-region consisting of 5 linked 3′-nucleosides; or
a 5′-region consisting of 3 linked 5′-nucleosides,
a central region consisting of 10 linked central region nucleosides, and
a 3′-region consisting of 3 linked 3′-nucleosides;
wherein each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.

9. The compound of claim 1 , wherein the first modified oligonucleotide consists of 14-20, 16-20, 16-18, 16, or 20 linked nucleosides.

10. The compound of claim 1 , wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one modified internucleoside linkage.

11. The compound of claim 10 , wherein each internucleoside linkage of the first modified oligonucleotide and/or the second modified oligonucleotide is a modified internucleoside linkage.

12. The compound of claim 10 wherein at least one internucleoside linkage of the first oligonucleotide and/or the second modified oligonucleotide is a phosphorothioate internucleoside linkage.

13. The compound of claim 12 wherein the first modified oligonucleotide and/or the second modified oligonucleotide comprises at least one unmodified phosphodiester internucleoside linkage.

14. The compound of claim 11 , wherein each internucleoside linkage of the first oligonucleotide is a phosphorothioate internucleoside linkage.

15. The compound of claim 1 , wherein the second modified oligonucleotide is at least 75%, at least 80%, at least 90%, or 100% complementary to the first modified oligonucleotide, over the length of the second modified nucleotide.

16. The compound of claim 1 , wherein the second modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 2 linked 5′-nucleosides,
a central region consisting of 4 linked central region nucleosides, and
a 3′-region consisting of 2 linked 3′-nucleosides; or
a 5′-region consisting of 4 linked 5′-nucleosides,
a central region consisting of 2 linked central region nucleosides, and
a 3′-region consisting of 3 linked 3′-nucleosides;
wherein each of the 5′-region nucleosides and each of the 3′-region comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.

17. The compound of claim 1 , wherein the second modified oligonucleotide consists of 6-10, 7-10, 8-10, 8-9, 7-9, 8, or 9 linked nucleosides.

18. The compound of claim 1 , wherein the first modified oligonucleotide or the second modified oligonucleotide comprises at least one modified nucleobase.

19. The compound of claim 18 , wherein the modified nucleobase is a 5′-Me cytosine.

20. The compound of claim 1 , wherein the 3′-most nucleobase of the second modified oligonucleotide is complementary to the 5′-most nucleobase of the first modified oligonucleotide.

21. The compound of claim 1 , wherein the compound comprises a conjugate group covalently attached to the first modified oligonucleotide or the second modified oligonucleotide.

22. The compound of claim 21 , wherein the conjugate group is covalently attached to the 3′-end or the 5′-end of the first modified oligonucleotide or the second modified oligonucleotide.

23. The compound of claim 21 , wherein the conjugate group consists of a conjugate linker and a conjugate moiety.

24. The compound of claim 23 , wherein the conjugate moiety is a lipid, a C 16 alkyl, or cholesterol.

25. The compound of claim 23 , wherein the conjugate linker is TCA, TEG, or hexylamino.

26. The compound of claim 1 , where the compound exists primarily as a duplex at or below 57° C., at or below 47° C., or at 37° C.

27. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

28. A method comprising administering to an animal the compound of claim 1 .

29. A method of treating a disease associated with an extra-hepatic nucleic acid target comprising administering to an individual having or at risk for developing a disease associated with the extra-hepatic nucleic acid target a therapeutically effective amount of the compound of claim 1 ; and thereby treating the disease associated with the extra-hepatic nucleic acid target.

30. The method of claim 29 , wherein the extra-hepatic nucleic acid target is a muscle target.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Oestergaard Michael
• Seth Punit P
• Rigo Frank
• Dwyer Chrissa A

Classifications

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12N2310/341

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

• C12N15/1137 Primary

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• A61K9/0085

  Brain, e.g. brain implants; Spinal cord · CPC title

• C12N15/113

  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