Compositions and Methods for Inhibiting Expression of TGF-BETA Receptor Genes

• US 20110119781A1
• Filed: 07/08/2009
• Published: 05/19/2011
• Est. Priority Date: 07/15/2008
• Status: Abandoned Application

• Current Assignee: Arrowhead Research Corporation
• Original Assignee: Arrowhead Research Corporation
• Inventors: Vamlocher, Hans-Peter, Tan, Pamela, Bramlage, Birgit, Hossbach, Markus
• Application Number:
  US13/054,111
• Publication Number:
  US 20110119781A1
• Time in Patent Office: Days
• US Class Current: 800/18
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C12N 15/1138 against receptors or cell surface proteins
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/3521 Methyl

Abstract

The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of a TGF-beta receptor type I gene, comprising an antisense strand having a nucleotide sequence which is less than 30 nucleotides in length and which is substantially complementary to at least a part of a TGF-beta receptor type I gene. The invention also relates to a pharmaceutical composition comprising the dsRNA or nucleic acid molecules or vectors encoding the same together with a pharmaceutically acceptable carrier; methods for treating diseases caused by the expression of a TGF-beta receptor type I gene using said pharmaceutical composition; and methods for inhibiting the expression of a TGF-beta receptor type I gene in a cell.

Claims

1-20. -20. (canceled)

21. A double-stranded ribonucleic acid molecule capable of inhibiting the expression of a human TGF-beta receptor type I gene in vitro by at least 80%.

22. A double-stranded ribonucleic acid molecule of claim 21 wherein the double-stranded ribonucleic acid molecule is less than 30 nucleotides in length.

23. A double-stranded ribonucleic acid molecule of claim 21, wherein said sense strand or antisense strand contains at least one modified nucleotide.

24. A double-stranded ribonucleic acid molecule of claim 23, wherein said modified nucleotide is selected from the group consisting of a 2′

-O-methyl modified nucleotide, a nucleotide comprising a 5′

-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group, a 2′

-deoxy-2′

-fluoro modified nucleotide, a 2′

-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′

-amino-modified nucleotide, a 2′

-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide.

25. A double-stranded ribonucleic acid molecule comprising a sense strand sequence selected from the group consisting of SEQ ID NOS:

1, 117, 103, 31, 81, 99, 23, 13, 29 and 7; and

an antisense strand sequence selected from the group consisting of SEQ ID NOS;

2, 118, 104, 32, 82, 100, 24, 14, 30 and 8.

26. A double-stranded ribonucleic acid molecule of claim 25 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

1/2 and 117/118.

27. A double-stranded ribonucleic acid molecule of claim 25 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

103/104 and 31/32.

28. A double-stranded ribonucleic acid molecule of claim 25 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

81/82 and 99/100.

29. A double-stranded ribonucleic acid molecule of claim 25 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

23/24 and 13/14.

30. A double-stranded ribonucleic acid molecule of claim 25 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

29/30 and 7/8.

37. A cell, tissue or non-human organism comprising the double-stranded ribonucleic acid molecule as defined in claim 25.

39. A pharmaceutical composition comprising the double-stranded ribonucleic acid molecule as defined in claim 25 and a pharmaceutically acceptable carrier, stabilizer or diluent.

31. A double-stranded ribonucleic acid molecule comprising a sense strand sequence selected from the group consisting of SEQ ID NOS:

151, 249, 261, 231, 275, 253, 211, 265, 181, 185, 209, 299, 295, 279 and 219; and

an antisense strand sequence selected from the group consisting of SEQ ID NOS;

152, 250, 262, 232, 276, 254, 212, 266, 182, 186, 210, 300, 296, 280 and 220.

32. A double-stranded ribonucleic acid molecule of claim 31 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

151/152 and 249/250.

33. A double-stranded ribonucleic acid molecule of claim 31 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

261/262, 231/232, and 275/276.

34. A double-stranded ribonucleic acid molecule of claim 31 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

253/254, 211/212, and 265/266.

35. A double-stranded ribonucleic acid molecule of claim 31 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

181/182, 185/186, and 209/210.

36. A double-stranded ribonucleic acid molecule of claim 31 comprising a sense/antisense sequence pair selected from the group consisting of SEQ ID NOS:

299/300, 295/296, 279/280 and 219/220.

38. A cell, tissue or non-human organism comprising the double-stranded ribonucleic acid molecule as defined in claim 31.

40. A pharmaceutical composition comprising the double-stranded ribonucleic acid molecule as defined in claim 31 and a pharmaceutically acceptable carrier, stabilizer or diluent.