Antisense modulation of tumor necrosis factor receptor 2 expression

• US 6,410,324 B1
• Filed: 04/27/2001
• Issued: 06/25/2002
• Est. Priority Date: 04/27/2001
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Bennett, C. Frank, Watt, Andrew T.
• Primary Examiner(s): LeGuyader, John L.
• Assistant Examiner(s): SCHMIDT, MARY M
• Application Number:
  US09/844,634
• Time in Patent Office: 424 Days
• Field of Search: 435/6, 435/325, 435/366, 435/375, 536/23.1, 536/24.5, 536/25.3, 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: C12N 15/1138 against receptors or cell surface proteins
• 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 2310/3341 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

Antisense compounds, compositions and methods are provided for modulating the expression of Tumor Necrosis Factor Receptor 2. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Tumor Necrosis Factor Receptor 2. Methods of using these compounds for modulation of Tumor Necrosis Factor Receptor 2 expression and for treatment of diseases associated with expression of Tumor Necrosis Factor Receptor 2 are provided.

Claims

1. A compound 8 to 30 nucleobases in length targeted to nucleobases 198 through 1472 of a coding region, or nucleobases 1512 through 3671 of a 3′

-untranslated region of a nucleic acid molecule encoding a human Tumor Necrosis Factor Receptor 2 (SEQ ID NO;

     3), or nucleobases 4477 through 8921 of an intron region encoding human Tumor Necrosis Factor Receptor 2 (SEQ ID NO;

     17), or nucleobases 70-1164 of a coding region or nucleobases 1726-3751 of a 3′

-untranslated region of a nucleic acid molecule encoding a mouse Tumor Necrosis Factor Receptor 2 (SEQ ID NO;

     10), or nucleobases 698-743 of an intron region of a nucleic acid molecule encoding murine Tumor Necrosis Factor Receptor 2 (SEQ ID NO;

98), wherein said compound specifically hybridizes with one or said regions and inhibits the expression of Tumor Necrosis Factor Receptor 2.

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

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

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

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

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

-O-methoxyethyl sugar moiety.

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

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

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

11. A composition comprising the 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 compound is an antisense oligonucleotide.

14. A method of inhibiting the expression of human or mouse Tumor Necrosis Factor Receptor 2 in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 1 so that expression of human or mouse Tumor Necrosis Factor Receptor 2 is inhibited.

3. A compound up to 50 nucleobases in length comprising at least an 8-nucleobases portion of SEQ ID NO:

20, 21 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 36, 39, 40, 41, 43, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 57, 58, 59, 60, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 117, 118, 119, 120, 121, 122, 123, 126, 127, 128, 129, 132, 133, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 167, 171, 173 or 174 which inhibits the expression of human or mouse Tumor Necrosis Factor Receptor 2.

15. The compound of claim 3 which is an antisense oligonucleotide.

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

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

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

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

-O-methoxyethyl sugar moiety.

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

21. The compound of claim 20 wherein the modified nucleobase is a 5-methylcytosine.

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

23. A composition comprising the compound of claim 3 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 compound is an antisense oligonucleotide.

26. A method of inhibiting the expression of human or murine Tumor Necrosis Factor Receptor 2 in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 3 so that expression of human or murine Tumor Necrosis Factor Receptor 2 is inhibited.