ANTISENSE OLIGONUCLEOTIDE MODULATION OF STAT3 EXPRESSION

• US 20110054003A1
• Filed: 04/23/2009
• Published: 03/03/2011
• Est. Priority Date: 02/06/2004
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Karras, James G.
• Granted Patent: US 8,183,363 B2
• Time in Patent Office: Days
• US Class Current: 514/44.A
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 15/1135 against oncogenes or tumor suppressor genes
• 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 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• 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
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Compounds, compositions and methods are provided for inhibiting the expression of human STAT3. The compositions comprise antisense oligonucleotides targeted to nucleic acids encoding STAT3. Methods of using these oligonucleotides for inhibition of STAT3 expression and for promotion of apoptosis are provided. Methods for treatment of diseases, particularly inflammatory diseases and cancers, associated with overexpression or constitutive activation of STAT3 or insufficient apoptosis are also provided.

Claims

1. A compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the nucleobase sequence of SEQ ID NO:

363.

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:

363.

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

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

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

7. The compound of claim 6, wherein the modified sugar is selected from the group consisting of a 2′

-O-(2-methoxyethyl), and a bicyclic 2′

-C, 4′

-C-oxymethylene linkage 4′

-(CH₂)_n—

O-2′

, wherein n is 1 or 2.

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

9. The compound of claim 8, wherein the modified nucleobase is a 5-methylcytosine.

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

a gap segment consisting of linked deoxyribonucleosides;

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.

11. The compound of claim 10, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxyribonucleosides;

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; and

wherein each internucleoside linkage is a phosphorothioate linkage; and

wherein each cytosine in said antisense oligonucleotide is a 5-methylcytosine.

12. The compound of claim 2, wherein the modified oligonucleotide consists of 20 linked nucleosides.

21. A method of inhibiting the expression of STAT3 in a cancer cell comprising contacting said cancer cell with the compound of claim 1, wherein expression of STAT3 is inhibited.

13. A composition comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the nucleobase sequence of SEQ ID NO:

363.

14. The composition of claim 13, wherein the modified oligonucleotide consists of a single-stranded modified oligonucleotide.

15. The composition of claim 13, wherein the modified oligonucleotide consists of 20 linked nucleosides.

16. A method comprising administering to an animal a compound comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 8 contiguous nucleobases of the nucleobase sequence of SEQ ID NO:

363.

17. The method of claim 16, wherein the animal is a human.

18. The method of claim 17, wherein administering the compound slows progression of cancer.

19. A method comprising identifying a human with cancer and administering to the human a therapeutically effective amount of a composition comprising a modified oligonucleotide consisting of 15 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 12 contiguous nucleobases of the nucleobase sequence of SEQ ID NO:

363.

20. The method of claim 19, wherein the administering suppresses induction of serum prostate specific antigen.