Antisense inhibition of Fas mediated signaling

• US 6,204,055 B1
• Filed: 04/12/1999
• Issued: 03/20/2001
• Est. Priority Date: 04/12/1999
• Status: Expired due to Fees

• Current Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Marcusson, Eric G., Dean, Nicholas M.
• Primary Examiner(s): Schwartzman, Robert A.
• Assistant Examiner(s): Lacourciere, Karen A
• Application Number:
  US09/290,640
• Time in Patent Office: 708 Days
• Field of Search: 435/6, 435/91.1, 435/91.3, 435/325, 435/375, 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• 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
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Compounds, compositions and methods are provided for inhibiting Fas mediated signaling. The compositions comprise antisense compounds targeted to nucleic acids encoding Fas, FasL and Fap-1. Methods of using these antisense compounds for inhibition of Fas, FasL and Fap-1 expression and for treatment of diseases, particularly autoimmune and inflammatory diseases and cancers, associated with overexpression or constitutive activation of Fas, FasL or Fap-1 are provided.

Claims

1. An antisense compound up to 30 nucleobases in length targeted to a nucleic acid molecule encoding Fas, wherein said antisense compound specifically hybridizes with said nucleic acid molecule and inhibits the expression of Fas and wherein said antisense compound has a sequence comprising at least an 8 nucleobase portion of SEQ ID NO:

11, 12, 14, 15, 16, 17, 19, 20, or 21.

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

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

4. The antisense compound of claim 3 wherein the modified internucleoside linkage is a phosphorothioate linkage.

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

6. The antisense compound of claim 5 wherein the modified sugar moiety is a 2′

-O-methoxyethyl moiety.

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

8. The antisense compound of claim 7 wherein modified nucleobase is a 5-methyl cytosine.

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

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

11. The composition of claim 10 further comprising a colloidal dispersion system.

12. The composition of claim 10 wherein the antisense compound is an antisense oligonucleotide.

13. A method of inhibiting the expression of Fas in cells or tissues comprising contacting said cells or tissues in vitro with the antisense compound of claim 1 so that expression of Fas is inhibited.

14. An antisense compound 8 to 30 nucleobases in length targeted to the coding region of a nucleic acid molecule encoding Fas, wherein said antisense compound inhibits the expression of said Fas and has a sequence comprising SEQ ID NO:

6, 7, 8, or 10.

15. The antisense compound of claim 14 which is an antisense oligonucleotide.

16. The antisense compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage.

17. The antisense compound of claim 16 wherein the modified internucleoside linkage is a phosphorothioate linkage.

18. The antisense compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

19. The antisense compound of claim 18 wherein the modified sugar moiety is a 2′

-O-methoxyethyl moiety.

20. The antisense compound of claim 15 wherein the antisense oligonucleotide comprises at least one modified nucleobase.

21. The antisense compound of claim 20 wherein modified nucleobase is a 5-methyl cytosine.

22. The antisense compound of claim 15 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

23. A composition comprising the antisense compound of claim 14 and a pharmaceutically acceptable carrier or diluent.

24. The composition of claim 23 further comprising a colloidal dispersion system.

25. The composition of claim 23 wherein the antisense compound is an antisense oligonucleotide.

26. A method of inhibiting the expression of Fas in cells or tissues comprising contacting said cells or tissues in vitro with the antisense compound of claim 14 so that expression of Fas is inhibited.

27. An antisense compound targeted to a nucleic acid molecule encoding Fas, wherein said antisense compound specifically hybridizes with said nucleic acid molecule and inhibits the expression of Fas and wherein said antisense compound has a sequence consisting of SEQ ID NO:

5 or 13.

28. The antisense compound of claim 27 which is an antisense oligonucleotide.

29. The antisense compound of claim 28 wherein the the antisense oligonucleotide comprises at least one modified internucleoside linkage.

30. The antisense compound of claim 29 wherein the modified internucleoside linkage is a phosphorothioate linkage.

31. The antisense compound of claim 28 wherein the antisense oligonucleotide comprises at least one modified sugar moiety.

32. The antisense compound of claim 31 wherein the modified sugar moiety is a 2′

-O-methoxyethyl sugar moiety.

33. The antisense compound of claim 28 wherein the the antisense oligonucleotide comprises at least one modified nucleobase.

34. The antisense compound of claim 33 wherein the modified nucleobase is a 5-methylcytosine.

35. The antisense compound of claim 28 wherein the antisense oligonucleotide is a chimeric oligonucleotide.

36. A composition comprising the antisense compound of claim 27 and a pharmaceutically acceptable carrier or diluent.

37. The composition of claim 36 further comprising a colloidal dispersion system.

38. The composition of claim 36 wherein the antisense compound is an antisense oligonucleotide.

39. A method of inhibiting the expression of Fas in cells or tissues comprising contacting said cells or tissues in vitro with the antisense compound of claim 27 so that expression of Fas is inhibited.