Modulation of stat5 expression

• US 8,722,873 B2
• Filed: 02/22/2010
• Issued: 05/13/2014
• Est. Priority Date: 11/06/2003
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Freier, Susan M., Karras, James G.
• Primary Examiner(s): Chong, Kimberly
• Application Number:
  US12/710,232
• Publication Number:
  US 20100311814A1
• Time in Patent Office: 1,541 Days
• Field of Search: None
• US Class Current: 536/24.5
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07K 14/4702 Regulators; Modulating activity
• 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 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy

Abstract

Compounds, compositions and methods are provided for modulating the expression of STAT5. The compositions comprise oligonucleotides, targeted to nucleic acid encoding STAT5. Methods of using these compounds for modulation of STAT5 expression and for diagnosis and treatment of diseases and conditions associated with expression of STAT5 are provided.

Claims

1. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having:

i) a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from the group consisting of the nucleobase sequences recited in SEQ ID NOs;

12, 15-21, 23, 25-30, 33, 34, 38, 40, 41, 45-52, 54-58, 62-74, 78-82, 85, 87, 155-157, 159-161, 163, 164, 166, 169, 170, 173-181, 184-186, 188, 189, 191, 194, 196-200, 202, 203, 205, 209-211, and 213;

or

ii) a nucleobase sequence consisting of the nucleobase sequence of SEQ ID NOs 13, 14, 22, 24, 31, 32, 35, 37, 39, 42-44, 53, 59-61, 75, 76, 83, 84, 86, 88, 89, 158, 162, 165, 167, 171, 172, 182, 183, 187, 190, 192, 193, 195, 201, 204, 206, 207, or 212.

2. The compound of claim 1, consisting of a single-stranded modified oligonucleotide.

3. The compound of claim 2, wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to SEQ ID NO:

4 or SEQ ID NO;

151.

4. The compound of claim 2, wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage.

5. The compound of claim 4, wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage.

6. The compound of claim 2, wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar.

7. The compound of claim 6, wherein at least one modified sugar is a bicyclic sugar.

8. The compound of claim 6, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl or a 4′

-(CH₂)_n—

O-2′

bridge, wherein n is 1 or 2.

9. The compound of claim 2, wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase.

10. The compound of claim 9, wherein the modified nucleobase is a 5-methylcytosine.

11. 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 nucleoside of each wing segment comprises a modified sugar.

12. The compound of claim 11, 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 nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar;

wherein each cytosine in said modified oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.

13. The compound of claim 12, wherein the modified oligonucleotide consists of 20 linked nucleosides.

14. A composition comprising

the compound of claim 1, or a salt thereof;

and

a pharmaceutically acceptable carrier or diluent.

15. The composition of claim 14, wherein said modified oligonucleotide consists of a single-stranded modified oligonucleotide.

16. The composition of claim 14, wherein the modified oligonucleotide consists of 20 linked nucleosides.

17. A method comprising administering to an animal the compound of claim 1.

18. The method of claim 17, wherein the animal is a human.

19. The method of claim 18, comprising co-administering the compound and a chemotherapeutic agent.

20. The method of claim 19, wherein the compound and the chemotherapeutic agent are administered concomitantly.

21. The method of claim 18, wherein the administering is topical, pulmonary, oral or parenteral.

22. A method comprising administering to a human a therapeutically effective amount of the composition of claim 14.

23. The method of claim 22, comprising co-administering the composition and a chemotherapeutic agent.

24. A compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of the nucleobase sequence recited in SEQ ID NOs:

168 or 208, 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 nucleoside of each wing segment comprises a modified sugar.