Conjugated antisense compounds and their use

Patent metadata

Field	Value
Publication number	US-12275940-B2
Application number	US-202318342409-A
Country	US
Kind code	B2
Filing date	Jun 27, 2023
Priority date	Dec 14, 2017
Publication date	Apr 15, 2025
Grant date	Apr 15, 2025

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 14-30 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.

2. The compound of claim 1 , wherein the first modified oligonucleotide has a nucleobase sequence that is at least 80% or 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 and/or the second modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.

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 selected from among cEt or LNA.

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 non-bicyclic sugar moiety comprising a 2′-MOE or 2′-OMe.

6. The compound of claim 1 , wherein the first modified oligonucleotide has a sugar motif comprising:
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.

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

8. The compound of claim 1 , wherein each internucleoside linkage of the first oligonucleotide is a phosphorothioate internucleoside linkage.

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

10. The compound of claim 1 , wherein each internucleoside linkage of the second modified oligonucleotide is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

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

12. The compound of claim 11 , wherein the conjugate group is covalently attached to the second modified oligonucleotide.

13. The compound of claim 12 , wherein the conjugate group is covalently attached to the 5′-end of the second modified oligonucleotide.

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

15. A method comprising administering to an animal the compound or pharmaceutical composition of claim 1 .

16. 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 or pharmaceutical composition of claim 1 ; and thereby treating the disease associated with the extra-hepatic nucleic acid target.

17. The compound of claim 1 , wherein the second modified oligonucleotide has a gapmer-like motif that does not support RNase H activity.

18. The compound of claim 11 , wherein the conjugate group is a peptide.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

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

Classifications

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C12N2310/3535

  Nitrogen · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title

• C12N2310/351

  Conjugate · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title