Antisense modulation of protein phosphatase 2 catalytic subunit beta expression

• US 6,602,713 B1
• Filed: 02/09/2001
• Issued: 08/05/2003
• Est. Priority Date: 02/09/2001
• Status: Expired due to Term

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Wyatt, Jacqueline
• Primary Examiner(s): McGarry, Sean
• Assistant Examiner(s): ZARA, JANE J
• Application Number:
  US09/780,045
• Time in Patent Office: 907 Days
• Field of Search: 435/6, 435/91.1, 435/455, 435/375, 536/23.1, 536/24.5, 536/25.3, 514/44
• US Class Current: 435/458
• 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 15/1137 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
• CPC Class Codes: C12Y 301/03016 Phosphoprotein phosphatase (3.1.3.16), i.e. calcineurin
• 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 Protein Phosphatase 2 catalytic subunit beta. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Protein Phosphatase 2 catalytic subunit beta. Methods of using these compounds for modulation of Protein Phosphatase 2 catalytic subunit beta expression and for treatment of diseases associated with expression of Protein Phosphatase 2 catalytic subunit beta are provided.

Claims

1. A compound 8 to 50 nucleobases in length targeted to nucleobases 567 through 586, nucleobases 596 through 615, nucleobases 624 through 643, nucleobases 740 through 759, nucleobases 763 through 782, nucleobases 862 through 881, nucleobases 885 through 932, or nucleobases 945 through 964 of a 5′

-untranslated region, nucleobases 983 through 1004 of a start codon region, nucleobases 1042 through 1091, nucleobases 1096 through 1115, nucleobases 1232 through 1251, nucleobases 1279 through 1303, nucleobases 1363 through 1382, nucleobases 1433 through 1487, nucleobases 1492 through 1511, nucleobases 1546 through 1582, nucleobases 1627 through 1666, nucleobases 1795 through 1824 of a coding region, nucleobases 1903 through 1928 of a stop codon region, or nucleobases 1952 through 1971, nucleobases 1975 through 1994, nucleobases 2069 through 2088, nucleobases 2113 through 2155, nucleobases 2164 through 2183, nucleobases 2202 through 2221, nucleobases 2257 through 2352, nucleobases 2370 through 2402, nucleobases 2407 through 2434, nucleobases 2444 through 2463, nucleobases 2482 through 2501, or nucleobases 2518 through 2537 of a 3′

-untranslated region of a nucleic acid molecule encoding Protein Phosphatase 2 catalytic subunit beta of SEQ ID NO;

3, or nucleobases 9 through 42, nucleobases 67 through 86, nucleobases 124 through 143, nucleobases 195 through 267, or nucleobases 272 through 297 of a 5′

-untranslated region, nucleobases 302 through 323 of a start codon region, nucleobases 361 through 410, nucleobases 415 through 434, nucleobases 551 through 570, nucleobases 598 through 622, nucleobases 682 through 701, nucleobases 752 through 806, nucleobases 811 through 830, nucleobases 865 through 901, nucleobases 946 through 985, nucleobases 1114 through 1143 of a coding region, or nucleobases 1270 through 1290, nucleobases 1335 through 1363, nucleobases 1383 through 1402, nucleobases 1410 through 1435, nucleobases 1439 through 1479, nucleobases 1483 through 1517, nucleobases 1534 through 1553, nucleobases 1575 through 1635, nucleobases 1650 through 1687, nucleobases 1708 through 1774, or nucleobases 1798 through 1817 of a 3′

-untranslated region of a nucleic acid molecule encoding Protein Phosphatase 2 catalytic subunit beta of SEQ ID NO;

10, wherein said compound specifically hybridizes with one of said regions and inhibits the expression of Protein Phosphatase 2 catalytic subunit beta.

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

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

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

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

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

-O-methoxyethyl sugar moiety.

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

8. The compound of claim 7 wherein the modified nucleobase is a 5-methylcytosine.

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

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

13. A method of inhibiting the expression of Protein Phosphatase 2 catalytic subunit beta in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 1 so that expression of Protein Phosphatase 2 catalytic subunit beta is inhibited.

14. A compound up to 50 nucleobases in length comprising at least a 15-nucleobase portion of SEQ ID NO:

17, 20, 21, 22, 23, 25, 26, 27, 28, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 53, 54, 55, 56, 57, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 81, 82, 86, 87, 88, 92, 24, 52, 58, 95, 97, 98, 101, 102, 103, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 125, 126, 129, 130, 132, 133 or 134 which inhibits the expression of Protein Phosphatase 2 catalytic subunit beta.

15. The compound of claim 14 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 method of inhibiting the expression of Protein Phosphatase 2 catalytic subunit beta in cells or tissues comprising contacting said cells or tissues in vitro with the compound of claim 14 so that expression of Protein Phosphatase 2 catalytic subunit beta is inhibited.

24. A composition comprising the compound of claim 14 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 compound is an antisense oligonucleotide.