Compositions and methods for modulating growth hormone receptor expression
The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with excess growth hormone using antisense compounds or oligonucleotides targeted to growth hormone receptor (GHR).
1. A method comprising administering to an animal a compound, or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent, wherein the compound consists of a conjugate group and a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is the nucleobase sequence of SEQ ID NO: 703 and an anion form of the compound has the following chemical structure:
2. The method of claim 1 , wherein the animal is a human.
3. A method of treating a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount of a compound, or a therapeutically effective amount of a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent, wherein the compound consists of a conjugate group and a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is the nucleobase sequence of SEQ ID NO: 703 and an anion form of the compound has the following chemical structure:
thereby treating the disease associated with excess growth hormone.
4. The method of claim 3 , wherein the disease associated with excess growth hormone is acromegaly.
5. The method of claim 3 , wherein the treatment reduces IGF-1 levels.
6. A method of preventing a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount of a compound, or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent, wherein the compound consists of a conjugate group and a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is the nucleobase sequence of SEQ ID NO: 703 and an anion form of the compound has the following chemical structure:
thereby preventing the disease associated with excess growth hormone.
7. The method of claim 6 , wherein the disease associated with excess growth hormone is acromegaly.
8. The method of claim 3 , comprising co-administering the compound or composition and a second agent.
9. The method of claim 8 , wherein the compound or composition and the second agent are administered concomitantly.
10. A method of reducing growth hormone receptor (GHR) levels in a human comprising administering to the human a therapeutically effective amount of a compound, or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent, wherein the compound consists of a conjugate group and a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is the nucleobase sequence of SEQ ID NO: 703 and an anion form of the compound has the following chemical structure:
thereby reducing GHR levels in the human.
11. The method of claim 10 , wherein the human has a disease associated with excess growth hormone.
12. The method of claim 11 , wherein the disease associated with excess growth hormone is acromegaly.
13. The method of claim 12 , comprising co-administering the compound or composition and a second agent.
14. The method of claim 13 , wherein the compound or composition and the second agent are administered concomitantly.
15. The method of any one of claim 1 , 3 , 6 , or 10 , wherein the compound is a salt.
16. The method of claim 15 , wherein the cation of the salt is sodium.
17. A compound consisting of a conjugate group and a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is the nucleobase sequence of SEQ ID NO: 703 and an anion form of the compound has the following chemical structure:
wherein each X is independently 0 or S.
18. The compound of claim 17 , wherein the modified oligonucleotide comprises at least one phosphorothioate internucleoside linkage.
19. The compound of claim 17 , wherein the modified oligonucleotide comprises at least six phosphorothioate internucleoside linkages.
20. The compound of claim 17 , wherein the modified oligonucleotide comprises at least eight phosphorothioate internucleoside linkages.
21. The compound of claim 17 , wherein the modified oligonucleotide comprises at least 10 phosphorothioate internucleoside linkages.
22. The compound of claim 17 , wherein the modified oligonucleotide comprises at least 12 phosphorothioate internucleoside linkages.
23. The compound of claim 17 , wherein the modified oligonucleotide comprises 13 phosphorothioate internucleoside linkages.
24. The compound of claim 17 , wherein the modified oligonucleotide comprises 15 phosphorothioate internucleoside linkages.
25. The compound of claim 17 , wherein the modified oligonucleotide comprises at least one block of at least six consecutive phosphorothioate internucleoside linkages.
26. The compound of claim 25 , wherein the at least one block of at least six consecutive phosphorothioate internucleoside linkages is located at the 3′ end of the modified oligonucleotide.
27. The compound of claim 25 , wherein the at least one block of at least six consecutive phosphorothioate internucleoside linkages is not located at the 3′ end of the modified oligonucleotide.
28. The compound of claim 25 , wherein the at least one block of at least six consecutive phosphorothioate internucleoside linkages is located within three nucleosides of the 3′ end of the modified oligonucleotide.
29. The compound of claim 25 , wherein the at least one block of at least six consecutive phosphorothioate internucleoside linkages is not located within three nucleosides of the 3′ end of the modified oligonucleotide.
30. The compound of claim 17 , wherein the modified oligonucleotide comprises at least one block of at least eight consecutive phosphorothioate internucleoside linkages.
31. The compound of claim 17 , wherein the modified oligonucleotide comprises at least one block of at least 10 consecutive phosphorothioate internucleoside linkages.
32. The compound of claim 17 , wherein the modified oligonucleotide comprises a block of 10 consecutive phosphorothioate internucleoside linkages.
33. The compound of claim 17 , wherein the modified oligonucleotide comprises a block of 11 consecutive phosphorothioate internucleoside linkages.
34. The compound of claim 17 , wherein the modified oligonucleotide comprises at least one block of at least 12 consecutive phosphorothioate internucleoside linkages.
35. The compound of claim 17 , wherein the modified oligonucleotide comprises a region with a defined pattern of phosphorothioate and phosphodiester internucleoside linkages.
36. The compound of claim 17 , wherein the modified oligonucleotide comprises a region with alternating phosphorothioate and phosphodiester internucleoside linkages.
37. The compound of claim 17 , wherein the modified oligonucleotide comprises a region with phosphorothioate internucleoside linkages.
38. The compound of claim 17 , wherein the modified oligonucleotide comprises at least a phosphodiester internucleoside linkage.
39. The compound of claim 17 , wherein an anion form of the compound has the following chemical structure:
40. The compound of claim 17 , wherein an anion form of the compound has the following chemical structure:
41. A composition comprising the compound of claim 17 and at least one of a pharmaceutically acceptable carrier and diluent.
42. A prodrug comprising the compound of claim 17 .
43. A method comprising administering to an animal a compound of claim 17 , or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent.
44. The method of claim 43 , wherein the animal is a human.
45. A method of treating a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount a compound of claim 17 or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent.
46. The method of claim 45 , wherein the disease associated with excess growth hormone is acromegaly.
47. The method of claim 45 , thereby reducing IGF-1 levels.
48. A method of preventing a disease associated with excess growth hormone in a human comprising administering to the human a therapeutically effective amount of a compound of claim 17 , or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent.
49. The method of claim 48 , wherein the disease associated with excess growth hormone is acromegaly.
50. The method of claim 48 , comprising co-administering the compound or composition and a second agent.
51. The method of claim 50 , wherein the compound or composition and the second agent are administered concomitantly.
52. A method of reducing growth hormone receptor (GHR) levels in a human comprising administering to the human a therapeutically effective amount of a compound of claim 17 or a composition comprising the compound and at least one of a pharmaceutically acceptable carrier and diluent.
53. The method of claim 52 , wherein the human has a disease associated with excess growth hormone.
54. The method of claim 53 , wherein the disease associated with excess growth hormone is acromegaly.
55. The method of claim 54 , comprising co-administering the compound or composition and a second agent.
56. The method of claim 55 , wherein the compound or composition and the second agent are administered concomitantly.