Modulation of eIF4E-BP2 expression

• US 7,468,431 B2
• Filed: 01/24/2005
• Issued: 12/23/2008
• Est. Priority Date: 01/22/2004
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Jain, Ravi, Dobie, Kenneth W., Bhanot, Sanjay
• Primary Examiner(s): MCGARRY, SEAN
• Application Number:
  US11/042,899
• Publication Number:
  US 20050196787A1
• Time in Patent Office: 1,429 Days
• Field of Search: None
• US Class Current: 536/24.5
• 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 compound comprising a modified oligonucleotide consisting of 15 to 80 linked nucleosides and having a nucleobase sequence which is at least 80% complementary to nucleotides 803-940 of SEQ ID NO:

4, wherein said compound inhibits the expression of human eIF4E-BP2 mRNA.

2. The compound of claim 1 which is 15 to 50 nucleobases in length.

3. The compound of claim 1 which is 15 to 30 nucleobases in length.

4. The compound of claim 1 wherein the modified oligonucleotide comprises an antisesnse oligonucleotide.

5. The compound of claim 1 wherein the modified oligonucleotide comprises a DNA oligonucleotide.

6. The compound of claim 1 wherein the modified oligonucleotide comprises an RNA oligonucleotide.

7. The compound of claim 1 wherein the modified oligonucleotide comprises an double-stranded oligonucleotide.

8. The compound of claim 1 wherein the modified oligonucleotide comprises a chimeric oligonucleotide.

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

10. The compound of claim 1 having at least 90% complementarity with nucleotides 803-940 of SEQ ID NO:

4.

11. The compound of claim 1 having at least 95% complementarity with nucleotides 803-940 of SEQ ID NO:

4.

12. The compound of claim 1 having at least 99% complementarity with nucleotides 803-940 of SEQ ID NO:

4.

13. The compound of claim 1 having at least one modified internucleoside linkage, modified sugar, or modified nucleobase.

14. The compound of claim 13 wherein at least one modified sugar comprises a 2′

-O-methoxyethyl.

15. The compound of claim 13 wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

16. A compound of claim 1 wherein said nucleobase sequence comprises at least a 13-nucleobase portion of SEQ ID NO:

60 or 61.

17. A compound of claim 1 wherein said nucleobase sequence is selected from the group consisting of SEQ ID NOs 60 or 61.

18. The compound of claim 1 wherein said nucleobase sequence consists of SEQ ID NO:

60 or 61.

19. The compound of claim 1, wherein said nucleobase sequence is complementary to nucleotides 851-870 or nucleotides 868-887, both of SEQ ID No:

4.

20. The compound of claim 1, wherein said nucleobase sequence is complementary to nucleotides 868-887 of SEQ ID NO:

4.

21. The compound of claim 15, wherein the modified nucleobase is a 5-methylcytosine.

22. The compound of claim 1 consisting of a single-stranded oligonucleotide.

23. The compound of claim 1, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides;

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each of said nucleosides of each of said wing segments comprises a modified sugar.

24. The compound of claim 23, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides;

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each of said nucleosides of each of said wing segments comprises a 2′

-O-methoxyethyl sugar; and

wherein each internucleoside linkage is a phosphorothioate linkage.

25. The compound of claim 23, wherein the modified oligonucleotide consists of 20 linked nucleosides.

30. The compound of claim 13, wherein the modified sugar is a bicyclic sugar.

26. A composition comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases of a nucleobase sequence selected from among the nucleobase sequences recited in SEQ ID NOs:

60 and 61 or a salt thereof and a pharmaceutically acceptable carrier or diluent.

27. The composition of claim 26, wherein the modified oliginucleotide is a single-stranded oligonucleotide.

28. The composition of claim 26, wherein the modified oligonucleotide consists of 20 linked nucleosides.

29. A composition comprising the compound of claim 26 or a salt thereof and a pharmaceutically acceptable carrier or diluent.