Claims
- 1. An antisense compound 8 to 30 nucleobases in length targeted to the 5′ untranslated region, coding region, intron:exon junction, intron region, exon region, translation termination codon region or 3′ untranslated region of a nucleic acid molecule encoding mdm2, wherein said antisense compound modulates the expression of mdm2.
- 2. The antisense compound of claim 1 wherein said antisense compound inhibits the expression of human mdm2.
- 3. The antisense compound of claim 1 which is an antisense oligonucleotide.
- 4. An antisense compound up to 30 nucleobases in length comprising at least an 8-nucleobase portion of SEQ ID NO: 3, 4, 5, 7, 10, 15, 17, 18, 19, 21, 36, 42, 52, 54, 59, 60, 61, 62, 64, 66, 67, 68, 69, 70, 72, 73, 74, 75, 77, 78, 80, 81, 84, 88, 90, 96, 98, 103, 105, 109, 111, 114, 117, 118, 120, 121, 124, 126, 127, 129, 130, 137, 145, 147, 151, 154, 156, 158, 160, 165, 171, 175, 177, 178, 180, 182, 183, 184, 186, 188, 189, 191, 192, 193, 195, 196, 197, 199, 200, 201, 203, 206, 210, 212, 215, 216, 218, 221, 225, 231, 235, 241, 243, 245, 246, 249, 251, 254, 256, 258, 260, 264, 268, or 373 which inhibits the expression of mdm2.
- 5. The antisense compound of claim 2 which is targeted to the 5′ untranslated region of the S-mdm2 transcript.
- 6. The antisense compound of claim 1 which contains at least one phosphorothioate intersugar linkage.
- 7. The antisense compound of claim 1 which has at least one 2′-O-methoxyethyl modification.
- 8. The antisense compound of claim 1 which contains at least one 5-methyl cytidine.
- 9. The antisense compound of claim 8 in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.
- 10. A pharmaceutical composition comprising the antisense compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
- 11. The pharmaceutical composition of claim 10 wherein said pharmaceutically acceptable carrier or diluent further comprises a lipid or liposome.
- 12. A method of modulating the expression of mdm2 in cells or tissues comprising contacting said cells or tissues with the antisense compound of claim 1.
- 13. A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the antisense compound of claim 2 or a pharmaceutical composition comprising said antisense compound.
- 14. A method of treating an animal having a disease or condition associated with mdm2 comprising administering to said animal a therapeutically or prophylactically effective amount of an antisense compound of claim 1.
- 15. The method of claim 14 wherein the disease or condition is associated with overexpression of mdm2 and the antisense compound inhibits the expression of mdm2.
- 16. The method of claim 14 wherein the disease or condition is associated with amplification of the mdm2 gene and the antisense compound inhibits the expression of mdm2.
- 17. The method of claim 14 wherein the disease or condition is a hyperproliferative condition and the antisense compound inhibits the expression of mdm2.
- 18. The method of claim 17 wherein the hyperproliferative condition is cancer.
- 19. The method of claim 18 wherein the cancer is a blood, bone, brain, breast, lung or a soft tissue cancer.
- 20. The method of claim 17 wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.
- 21. The method of claim 14 wherein said antisense compound is administered in combination with a chemotherapeutic agent to overcome drug resistance.
- 22. An antisense compound up to 30 nucleobases in length targeted to the translational start site of a nucleic acid molecule encoding human mdm2, wherein said antisense compound inhibits the expression of said human mdm2 and comprises at least an 8-nucleobase portion of SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 69, SEQ ID NO: 70 or SEQ ID NO: 72.
- 23. The antisense compound of claim 22 which contains at least one phosphorothioate intersugar linkage.
- 24. The antisense compound of claim 22 which has at least one 2′-O-methoxyethyl modification.
- 25. The antisense compound of claim 22 which contains at least one 5-methyl cytidine.
- 26. The antisense compound of claim 25 in which every 2′-O-methoxyethyl modified cytidine residue is a 5-methyl cytidine.
- 27. A pharmaceutical composition comprising the antisense compound of claim 22 and a pharmaceutically acceptable carrier or diluent.
- 28. The pharmaceutical composition of claim 27 wherein said pharmaceutically acceptable carrier or diluent comprises a lipid or liposome.
- 29. A method of modulating the expression of human mdm2 in cells or tissues comprising contacting said cells or tissues with the antisense compound of claim 22.
- 30. A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the antisense compound of claim 22.
- 31. A method of reducing hyperproliferation of human cells comprising contacting proliferating human cells with the pharmaceutical composition of claim 27.
- 32. A method of treating an animal having a disease or condition associated with mdm2 comprising administering to said animal a therapeutically or prophylactically effective amount of the antisense compound of claim 22.
- 33. The method of claim 32 wherein the disease or condition is associated with overexpression of mdm2 and the antisense compound inhibits the expression of mdm2.
- 34. The method of claim 32 wherein the disease or condition is associated with amplification of the mdm2 gene and the antisense compound inhibits the expression of mdm2.
- 35. The method of claim 32 wherein the disease or condition is a hyperproliferative condition and the antisense compound inhibits the expression of mdm2.
- 36. The method of claim 35 wherein the hyperproliferative condition is cancer.
- 37. The method of claim 36 wherein the cancer is a blood, bone, brain, breast, lung or a soft tissue cancer.
- 38. The method of claim 35 wherein the hyperproliferative condition is psoriasis, fibrosis, atherosclerosis or restenosis.
- 39. The method of claim 32 wherein said antisense compound is administered in combination with a chemotherapeutic agent to overcome drug resistance.
- 40. A method of modulating apoptosis in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that apoptosis is modulated.
- 41. A method of modulating apoptosis in cells or tissues comprising contacting said cells or tissues with the compound of claim 22 so that apoptosis is modulated.
- 42. A method of inducing the expression of p21 in cells or tissues comprising contacting said cell with the compound of claim 1 so that p21 expression is increased.
- 43. A method of inducing the expression of p21 in cells or tissues comprising contacting said cells or tissues with the compound of claim 22 so that p21 expression is increased.
- 44. An oligonucleotide comprising at least one nucleotide comprising a heterocycle member covalently bound to a substituted sugar member which is further covalently bound through at least one linker to a sugar moiety member of a second nucleotide, said at least one modified nucleotide described according to structure I;
- 45. The oligonucleotide according to claim 44 wherein G is O and R4 is 2′-O-dimethylamine oxyethylene and the Base is according to structure II;
Wherein R10 is a bond to the sugar, j is O, q is 3′-O-(2-methoxyethyl).
- 46. The oligonucleotide according to claim 44 wherein said nucleotide is according to structure IV;
- 47. The oligonucleotide according to claim 44 where G is oxygen and R11 is selected from the group comprising;
- 48. The oligonucleotide according to claim 44 wherein the Base is according to structure V;
- 49. The oligonucleotide according to claim 44 further associated with a pharmaceutically acceptable carrier, diluent, prodrug or lubricant.
- 50. The oligonucleotide according to claim 44 which is targeted to a nucleic acid encoding mdm2.
Parent Case Info
[0001] This application is a continuation-in-part of U.S. patent application Ser. No. 09/752,983, filed Jan. 2, 2001, which is a continuation of U.S. patent application Ser. No. 09/280,805, filed Mar. 26, 1999, now issued as U.S. Pat. No. 6,184,212, which is a continuation in part of U.S. patent application Ser. No. 09/048,810 filed Mar. 26, 1998, now issued as U.S. Pat. No. 6,238,921.
Continuations (1)
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Number |
Date |
Country |
Parent |
09280805 |
Mar 1999 |
US |
Child |
09752983 |
Jan 2001 |
US |
Continuation in Parts (2)
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Number |
Date |
Country |
Parent |
09752983 |
Jan 2001 |
US |
Child |
10005344 |
Dec 2001 |
US |
Parent |
09048810 |
Mar 1998 |
US |
Child |
09280805 |
Mar 1999 |
US |