Oligomeric compounds for reducing DMPK expression

Patent metadata

Field	Value
Publication number	US-11833221-B2
Application number	US-202217823854-A
Country	US
Kind code	B2
Filing date	Aug 31, 2022
Priority date	Sep 1, 2021
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

Provided are oligomeric compounds, methods, and pharmaceutical compositions for DMPK the amount or activity of DMPK RNA in a cell or animal, and in certain instances reducing the amount of DMPK protein in a cell or animal. Such oligomeric compounds, methods, and pharmaceutical compositions are useful to treat type 1 myotonic dystrophy.

First claim

The invention claimed is:

1. A modified oligonucleotide according to the following chemical structure:

or a salt thereof.

2. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: T ks T ko m C ko m C ds C ys G ds A ds A ds T ds G ds T ds m C ds m C ds G ko A ks m C k (SEQ ID NO: 13), wherein:
A=an adenine nucleobase,
m C=a 5-methylcytosine nucleobase,
C=a cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
y=a 2′-OMe sugar moiety,
k=a cEt sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.

3. The oligomeric compound of claim 2 comprising a conjugate group.

4. The oligomeric compound of claim 3 , wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

5. The oligomeric compound of claim 4 , wherein the conjugate moiety is a cell-targeting moiety.

6. The oligomeric compound of claim 5 , wherein the cell-targeting moiety binds a cell surface receptor on a skeletal muscle cell.

7. The oligomeric compound of claim 6 , wherein the cell-targeting moiety is selected from a carbohydrate, an antibody, and an antibody fragment.

8. A population of oligomeric compounds of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.

9. A pharmaceutical composition of an oligomeric compound of claim 2 and a pharmaceutically acceptable diluent.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

11. An oligomeric compound according to the following chemical structure:

or a salt thereof wherein Y and Z are from H and a conjugate group, wherein at least one of Y and Z is a conjugate group.

12. The oligomeric compound of claim 11 , wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

13. The oligomeric compound of claim 11 , wherein the conjugate group comprises C 10 -C 24 alkyl.

14. The oligomeric compound of claim 12 , wherein the conjugate moiety is a cell-targeting moiety.

15. The oligomeric compound of claim 14 , wherein the cell-targeting moiety binds a cell surface receptor on a skeletal muscle cell.

16. The oligomeric compound of claim 14 , wherein the cell-targeting moiety is selected from a carbohydrate and an antibody.

17. The oligomeric compound of claim 14 , wherein the cell-targeting moiety is an antibody or an antibody fragment that binds a transferrin receptor.

18. A population of oligomeric compounds of claim 11 , wherein all of the phosphorothioate internucleoside linkages of the oligomeric compound are stereorandom.

19. A pharmaceutical composition of an oligomeric compound of claim 11 and a pharmaceutically acceptable diluent.

20. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

21. An oligomeric compound according to the following chemical structure:

wherein Y and Z are selected from H and a conjugate group, wherein at least one of Y and Z is a conjugate group.

22. The oligomeric compound of claim 21 , wherein the conjugate group comprises a conjugate moiety and a conjugate linker.

23. The oligomeric compound of claim 21 , wherein the conjugate group comprises C 10 -C 24 alkyl.

24. The oligomeric compound of claim 22 , wherein the conjugate moiety is a cell-targeting moiety.

25. The oligomeric compound of claim 24 , wherein the cell-targeting moiety binds a cell surface receptor on a skeletal muscle cell.

26. The oligomeric compound of claim 24 , wherein the cell-targeting moiety is selected from a carbohydrate and an antibody.

27. The oligomeric compound of claim 24 , wherein the cell-targeting moiety is an antibody or an antibody fragment that binds a transferrin receptor.

28. A population of oligomeric compounds of claim 21 , wherein all of the phosphorothioate internucleoside linkages of the oligomeric compound are stereorandom.

29. A pharmaceutical composition of an oligomeric compound of claim 21 and a pharmaceutically acceptable diluent.

30. The pharmaceutical composition of claim 29 , wherein the pharmaceutically acceptable diluent is water or phosphate-buffered saline.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Rigo Frank
• Dwyer Chrissa A

Classifications

• A61K47/6849 Primary

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K47/6807

  the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense · CPC title

• C12N15/1137 Primary

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

• C12N2310/315

  Phosphorothioates · CPC title