Modulation of eIF4E-BP2 expression

• US 8,067,386 B2
• Filed: 11/19/2008
• Issued: 11/29/2011
• Est. Priority Date: 01/22/2004
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Jain, Ravi, Dobie, Kenneth W., Bhanot, Sanjay
• Primary Examiner(s): McGarry; Sean
• Application Number:
  US12/274,030
• Publication Number:
  US 20090082302A1
• Time in Patent Office: 1,105 Days
• Field of Search: None
• US Class Current: 514/44.A
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C12N 15/113 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 Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

Compounds, compositions and methods are provided for modulating the expression of eIF4E-BP2. The compositions comprise oligonucleotides, targeted to nucleic acid encoding eIF4E-BP2. Methods of using these compounds for modulation of eIF4E-BP2 expression and for diagnosis and treatment of diseases and conditions associated with expression of eIF4E-BP2 are provided.

Claims

1. A pharmaceutical composition comprising a modified antisense compound 13 to 80 nucleobases in length targeted to a nucleic acid molecule encoding eIF4E-BP2, wherein said compound has at least an 8 nucleobase portion 100% complementary within nucleotides 1393-1599 of SEQ ID NO:

4 encoding eIF4E-BP2, wherein said compound has at least 95% complementarity with SEQ ID NO;

4 and inhibits the expression of eIF4E-BP2 mRNA; and

a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1, wherein said antisense compound is 13 to 50 nucleobases in length.

3. The pharmaceutical composition of claim 1, wherein said antisense compound is 15 to 30 nucleobases in length.

4. The pharmaceutical composition of claim 1, wherein said antisense compound comprises an oligonucleotide.

5. The pharmaceutical composition of claim 1, wherein said antisense compound comprises a DNA oligonucleotide.

6. The pharmaceutical composition of claim 1, wherein said antisense compound comprises an RNA oligonucleotide.

7. The pharmaceutical composition of claim 1, wherein said antisense compound is a double-stranded oligonucleotide.

8. The pharmaceutical composition of claim 1, wherein said antisense compound comprises a chimeric oligonucleotide.

9. The pharmaceutical composition of claim 1 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.

10. The pharmaceutical composition of claim 1, wherein said antisense compound has at least 99% complementarity with said nucleic acid molecule encoding eIF4E-BP2.

11. The pharmaceutical composition of claim 1, wherein said antisense compound has at least one modified internucleoside linkage, sugar moiety, or nucleobase.

12. The pharmaceutical composition of claim 1, wherein said antisense compound has at least one 2′

-O-methoxyethyl sugar moiety.

13. The pharmaceutical composition of claim 1, wherein said antisense compound has at least one phosphorothioate internucleoside linkage.

17. The pharmaceutical composition of claim 1, wherein said antisense compound has 100% complementarity with said nucleic acid molecule encoding eIF4E-BP2.

14. A modified antisense compound 13 to 80 nucleobases in length targeted to a nucleic acid molecule encoding eIF4E-BP2, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

72, 74, 75, 76, or 77 and inhibits the expression of eIF4E-BP2 mRNA.

15. The antisense compound of claim 14, wherein said antisense compound has a sequence selected from the group consisting of SEQ ID NOs:

72, 74, 75, 76, and 77.

16. The antisense compound of claim 15, wherein said antisense compound has the sequence of SEQ ID NO:

75.

18. The antisense compound of claim 14, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

72.

19. The antisense compound of claim 14, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

74.

20. The antisense compound of claim 14, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

75.

21. The antisense compound of claim 14, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

76.

22. The antisense compound of claim 14, wherein said antisense compound comprises at least a 13-nucleobase portion of SEQ ID NO:

77.

23. The antisense compound of claim 15, wherein said antisense compound has the sequence of SEQ ID NO:

72.

24. The antisense compound of claim 15, wherein said antisense compound has the sequence of SEQ ID NO:

74.

25. The antisense compound of claim 15, wherein said antisense compound has the sequence of SEQ ID NO:

76.

26. The antisense compound of claim 15, wherein said antisense compound has the sequence of SEQ ID NO:

77.

27. The antisense compound of claim 14, wherein said compound is a double-stranded oligonucleotide.

28. The antisense compound of claim 14, wherein said compound is a chimeric oligonucleotide.

29. The antisense compound of claim 15, wherein said compound is a double-stranded oligonucleotide.

30. The antisense compound of claim 15, wherein said compound is a chimeric oligonucleotide.

31. A modified antisense compound 13 to 80 nucleobases in length targeted to a nucleic acid molecule encoding eIF4E-BP2, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

71, 72, 73, 74, 75, 76, or 77 and inhibits the expression of eIF4E-BP2 mRNA.

32. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

71.

33. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

72.

34. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

73.

35. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

74.

36. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

75.

37. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

76.

38. The modified antisense compound of claim 31, wherein said antisense compound comprises at least a 13 nucleobase portion 100% complementary within SEQ ID NO:

77.

39. The antisense compound of claim 31, wherein said antisense compound has the sequence of SEQ ID NO:

71.

40. The antisense compound of claim 31, wherein said antisense compound has the sequence of SEQ ID NO:

73.

41. The antisense compound of claim 31, wherein said compound is a double-stranded oligonucleotide.

42. The antisense compound of claim 31, wherein said compound is a chimeric oligonucleotide.

43. A modified antisense compound 13 to 80 nucleobases in length targeted to a nucleic acid molecule encoding eIF4E-BP2, wherein said compound has at least an 8 nucleobase portion 100% complementary within nucleotides 1393-1599 of SEQ ID NO:

4 encoding eIF4E-BP2, wherein said compound has at least 95% complementarity with SEQ ID NO;

4 and inhibits the expression of eIF4E-BP2 mRNA, wherein said compound is a double-stranded oligonucleotide or comprises a chimeric oligonucleotide.

44. The modified antisense compound of claim 43, wherein said compound is a double-stranded oligonucleotide.

45. The modified antisense compound of claim 43, wherein said compound is a chimeric oligonucleotide.

46. The modified antisense compound of claim 43 which is 13 to 50 nucleobases in length.

47. The modified antisense compound of claim 43 which is 15 to 30 nucleobases in length.

48. The modified antisense compound of claim 43 comprising a DNA oligonucleotide.

49. The modified antisense compound of claim 43 comprising an RNA oligonucleotide.

50. The modified antisense compound of claim 43 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.

51. The modified antisense compound of claim 43 having at least 99% complementarity with said nucleic acid molecule encoding eIF4E-BP2.

52. The modified antisense compound of claim 43 having 100% complementarity with said nucleic acid molecule encoding eIF4E-BP2.

53. The modified antisense compound of claim 43 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.

54. The antisense compound of claim 43 having at least one 2′

-O-methoxyethyl sugar moiety.

55. The antisense compound of claim 43 having at least one phosphorothioate internucleoside linkage.