Antisense inhibition of focal adhesion kinase expression

• US 6,133,031 A
• Filed: 08/19/1999
• Issued: 10/17/2000
• Est. Priority Date: 08/19/1999
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Monia, Brett P., Gaarde, William A.
• Primary Examiner(s): Elliott, George C.
• Assistant Examiner(s): Lacourciere, Karen A
• Application Number:
  US09/377,310
• Time in Patent Office: 425 Days
• Field of Search: 435/6, 435/91.1, 435/91.3, 435/375, 435/325, 536/23.1, 536/23.2, 536/24.5, 536/24.3, 536/24.31, 536/24.33, 514/44
• US Class Current: 435/375
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-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

Abstract

Compounds, compositions and methods are provided for inhibiting FAK mediated signaling. The compositions comprise antisense compounds targeted to nucleic acids encoding FAK. Methods of using these antisense compounds for inhibition of FAK expression and for treatment of diseases, particularly cancers, associated with overexpression or constitutive activation of FAK are provided.

Claims

1. An antisense compound 8 to 30 nucleobases in length targeted to nucleobases 1-120 of the 5'"'"'-untranslated region, nucleobases 150-230 of the 5'"'"'-untranslated region, translational termination region or nucleobases 3424-3679 of the 3'"'"'-untranslated region of a nucleic acid molecule encoding human focal adhesion kinase (SEO ID NO:

1), wherein said antisense compound inhibits the expression of said focal adhesion kinase.

2. The antisense compound of claim 1 which is an antisense oligonucleotide.

3. The antisense compound of claim 2 wherein the antisense oligonucleotide has a sequence comprising SEQ ID NO:

3, 4, 6, 7, 8, 9, 16, 17, 18, 20 or 23.

4. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.

5. The antisense compound of claim 4 wherein the modified internucleoside linkage is a phosphorothioate linkage.

6. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

7. The antisense compound of claim 6 wherein the modified sugar moiety is a 2'"'"'-O-methoxyethyl moiety.

8. The antisense compound of claim 2 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

9. The antisense compound of claim 8 wherein the modified nucleobase is a 5-methyl cytosine.

10. The antisense compound of claim 2 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

11. A composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

12. The composition of claim 11 further comprising a colloidal dispersion system.

13. The composition of claim 11 wherein the antisense compound is an antisense oligonucleotide.

14. A method of inhibiting the expression of human focal adhesion kinase in cells or tissues comprising contacting said cells or tissues with the antisense in vitro compound of claim 1 so that expression of focal adhesion kinase is inhibited.

15. An antisense compound up to 30 nucleobases in length targeted to the coding region of a nucleic acid molecule encoding human focal adhesion kinase, wherein said antisense compound inhibits the expression of said focal adhesion kinase and has a sequence comprising at least an 8 nucleobasic portion of SEQ ID NO:

11, 12, 14, 15, 30, 31 or 33.

16. The antisense compound of claim 15 which is an antisense oligonucleotide.

17. The antisense compound of claim 16 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.

18. The antisense compound of claim 17 wherein the modified internucleoside linkage is a phosphorothioate linkage.

19. The antisense compound of claim 16 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

20. The antisense compound of claim 19 wherein the modified sugar moiety is a 2'"'"'-O-methoxyethyl moiety.

21. The antisense compound of claim 16 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

22. The antisense compound of claim 21 wherein the modified nucleobase is a 5-methyl cytosine.

23. The antisense compound of claim 16 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

24. A composition comprising the antisense compound of claim 15 and a pharmaceutically acceptable carrier or diluent.

25. The composition of claim 24 further comprising a colloidal dispersion system.

26. The composition of claim 24 wherein the antisense compound is an antisense oligonucleotide.

27. A method of inhibiting the expression of human focal adhesion kinase in cells or tissues comprising contacting said cells or tissues in vitro with the antisense compound of claim 15 so that expression of focal adhesion kinase is inhibited.

28. A method of inhibiting neovascularization in the eye associated with expression of focal adhesion kinase in an animal comprising intravitreally administering to said animal a therapeutically or prophylactically effective amount of the antisense compound of claim 3 or 15 targeted to a nucleic acid molecule encoding human focal adhesion kinase wherein said antisense compound inhibits the expression of human focal adhesion kinase.

29. An in vitro method of inhibiting migration of cells associated with expression of focal adhesion kinase comprising administering to said cells a therapeutically or prophylactically effective amount of an antisense compound 8 to 30 nucleobases in length targeted to a nucleic acid molecule encoding human focal adhesion kinase comprising SEQ ID NO:

18 wherein said antisense compound inhibits the expression of human focal adhesion kinase.