WO2008109506B1 - Nucleic acid compounds for inhibiting jun gene expression and uses thereof - Google Patents
Nucleic acid compounds for inhibiting jun gene expression and uses thereofInfo
- Publication number
- WO2008109506B1 WO2008109506B1 PCT/US2008/055627 US2008055627W WO2008109506B1 WO 2008109506 B1 WO2008109506 B1 WO 2008109506B1 US 2008055627 W US2008055627 W US 2008055627W WO 2008109506 B1 WO2008109506 B1 WO 2008109506B1
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- WO
- WIPO (PCT)
- Prior art keywords
- strand
- molecule
- human
- mdrna
- nucleotides
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
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- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Oncology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing JUN gene expression. An mdRNA of this disclosure comprises at least three strands that combine to form at least two non-overlapping double-stranded regions separated by a nick or gap wherein one strand is complementary to a JUN mRNA. In addition, the meroduplex may have at least one uridine substituted with a 5-methyluridine, a nucleoside replaced with a locked nucleic acid, or optionally other modifications, and any combination thereof. Also provided are methods of decreasing expression of a JUN gene in a cell or in a subject to treat a JUN-related disease.
Claims
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of any one of human cJUN, JUNB, or JUND mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of any one human cJUN mRNA as set forth in SEQ ID NO: 1158, human JUNB mRNA as set forth in SEQ ID NO: 1481, or human JUND mRNA as set forth in SEQ ID NO: 1658, and a second strand and a third strand that is each complementary to non-overlapping regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap.
2. The mdRNA molecule of claim 1 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
3. The mdRNA molecule of claim 1 wherein the gap comprises from 1 to 10 unpaired nucleotides.
4. The mdRNA molecule of claim 1 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
5. The mdRNA molecule of claim 1 wherein the mdRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
6. The mdRNA molecule of claim 1 wherein the mdRNA contains an overhang of one to four nucleotides on at least one 3 '-end that is not part of the gap or has a blunt end at one or both ends of the mdRNA.
7. An mdRNA molecule that down regulates the expression of any one of human cJUN, JUNB, or JUND mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of any one of human cJUN mRNA as set forth in SEQ ID NO: 1158, human JUNB mRNA as set forth in SEQ ID NO: 1481, or human JUND mRNA as set forth in SEQ ID NO: 1658, and a second strand and a third strand that is each complementary to non-overlapping
85 regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap, and wherein at least one pyrimidine of the mdRNA molecule is a pyrimidine nucleoside according to Formula I or II:
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted Ci-C10 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-Ci0 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-C10 alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡, or heterocyclo group,
R and R are each independently a hydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and
R5 and R8 are each independently O or S.
8. The mdRNA molecule of claim 7 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
9. The mdRNA molecule of claim 7 wherein the gap comprises from 1 to 10 unpaired nucleotides.
10. The mdRNA molecule of claim 7 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
86
11. The mdRNA molecule of claim 7 wherein at least one R2 is selected from the group consisting of 2'-0-(Ci-C5) alkyl, 2'-O-methyl, 2'-OCH2OCH2CH3, 2'-OCH2CH2OCH3, 2'-0-allyl, and fluoro.
12. The mdRNA molecule of claim 7 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
13. The mdRNA molecule of claim 7 wherein the mdRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
14. The mdRNA molecule of claim 7 wherein contains an overhang of one to four nucleotides on at least one 3 '-end that is not a part of the gap or the dsRNA molecule has a blunt end on one or both ends of the mdRNA molecule.
15. An mdRNA molecule that down regulates the expression of any one of human cJUN, JUNB, or JUND mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of any one of human cJUN mRNA as set forth in SEQ ID NO: 1158, human JUNB mRNA as set forth in SEQ ID NO: 1481, or human JUND mRNA as set forth in SEQ ID NO: 1658, and a second strand and a third strand that is each complementary to non-overlapping regions of the first strand, wherein the second strand and third strand can anneal with the first strand to form at least two double-stranded regions spaced apart by a nick or a gap, and wherein the double-stranded regions have a combined length of about 15 base pairs to about 40 base pairs.
16. The mdRNA molecule of claim 15 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
17. The mdRNA molecule of claim 15 wherein the gap comprises from 1 to 10 unpaired nucleotides.
87
18. The mdRNA molecule of claim 15 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human cJUN nucleic acid sequence as set forth in any one of SEQ ID NOS: 1159-1342, or human JUNB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1482- 1582, or human JUND nucleic acid sequence as set forth in any one of SEQ ID NOS: 1659- 1760.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human cJUN nucleic acid sequence as set forth in any one of SEQ ID NOS: 1343-1480, or human JUNB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1583- 1657, or human JUND nucleic acid sequence as set forth in any one of SEQ ID NOS:1761-1838.
21. A method for reducing the expression of a human JUN gene, comprising administering an mdRNA molecule according to any one of claims 1-20 to a cell expressing a human cJUN, JUNB, or JUND gene, wherein the mdRNA molecule reduces the expression of the human cJUN, JUNB, or JUND gene in the cell.
22. The method according to claim 21 wherein the cell is a human cell.
23. Use of an mdRNA as defined in any one of the preceding claims for the manufacture of a medicament for use in the therapy of a hyperproliferative or inflammatory disease.
24. A double-stranded ribonucleic acid (dsRNA) molecule that down regulates the expression of any one of human cJUN, JUNB, or JUND mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of any one of human cJUN mRNA as set forth in SEQ ID NO: 1158, human JUNB mRNA as set forth in SEQ ID NO: 1481, or human JUND mRNA as set forth in SEQ ID NO: 1658, and a second strand that is complementary to the first strand, and wherein upon annealing of the first strand and the second strand the dsRNA has a 3' overhang and a blunt end.
88
25. The dsRNA molecule of claim 24 wherein the first strand is from 27 to 35 nucleotides in length.
26. The dsRNA molecule of claim 24 wherein the dsRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
27. The dsRNA molecule of claim 24 wherein the dsRNA molecule comprises at least one locked nucleic acid (LNA) molecule, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
28. The dsRNA molecule of claim 24 wherein the 3'-overhang has from one to four nucleotides and is on the first strand.
29. The dsRNA molecule of claim 24 wherein the dsRNA molecule has a 5'-terminal end comprising a hydroxyl or a phosphate.
30. A dsRNA molecule that down regulates the expression of any one of human cJUN, JUNB, or JUND mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of any one of human cJUN mRNA as set forth in SEQ ID NO: 1158, human JUNB mRNA as set forth in SEQ ID NO: 1481, or human JUND mRNA as set forth in SEQ ID NO: 1658, and a second strand that is complementary to the first strand, and wherein upon annealing of the first strand and the second strand the dsRNA has a 3' overhang and a blunt end, and wherein at least one pyrimidine of the dsRNA molecule comprises a pyrimidine nucleoside according to Formula I or II:
89 R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted Ci-Ci0 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-Ci0 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-Ci0 alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡N, or heterocyclo group,
R3 and R4 are each independently a hydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and
R5 and R8 are each independently O or S.
31. The dsRNA molecule of claim 30 wherein the first strand is from 27 to 35 nucleotides in length.
32. The dsRNA molecule of claim 30 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
33. The dsRNA molecule of claim 30 wherein at least one R2 is selected from the group consisting of 2'-O-(CrC5) alkyl, 2'-O-methyl, 2'-OCH2OCH2CH3, 2'-OCH2CH2OCH3, 2'-0-allyl, and 2'-fluoro.
34. The dsRNA molecule of claim 30 wherein the dsRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
35. The dsRNA molecule of claim 30 wherein the dsRNA molecule comprises at least one LNA, deoxy nucleotide, G clamp, 2'-sugar modification, modified internucleoside linkage, or any combination thereof.
36. The dsRNA molecule of claim 30, wherein the 3'-overhang has from one to four nucleotides and is on the first strand.
37. A method for reducing the expression of a human JUN gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to
90 a cell expressing a human cJUN, JUNB, or JUND gene, wherein the dsRNA molecule reduces the expression of the human cJUN, JUNB, or JUND gene in the cell.
38. The method according to claim 37 wherein the cell is a human cell.
39. Use of a dsRNA molecule as defined in any one of claims 24-38 for the manufacture of a medicament for use in the therapy of a hyperproliferative or inflammatory disease.
91
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/552,082 US20100105134A1 (en) | 2007-03-02 | 2009-09-01 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
US13/327,545 US20130011922A1 (en) | 2007-03-02 | 2011-12-15 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US93494007P | 2007-03-02 | 2007-03-02 | |
US60/934,940 | 2007-03-02 | ||
US93493007P | 2007-03-16 | 2007-03-16 | |
US60/934,930 | 2007-03-16 | ||
US1516607P | 2007-12-19 | 2007-12-19 | |
US61/015,166 | 2007-12-19 |
Related Parent Applications (1)
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PCT/US2008/055697 Continuation-In-Part WO2008109547A2 (en) | 2007-03-02 | 2008-03-03 | Nucleic acid compounds for inhibiting tymp gene expression and uses thereof |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2008/055572 Continuation-In-Part WO2008106664A2 (en) | 2007-03-01 | 2008-02-29 | Human behavioral modeling and simulation framework |
AU2009212920A Division AU2009212920A1 (en) | 2007-03-02 | 2009-09-01 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
US12/552,082 Continuation-In-Part US20100105134A1 (en) | 2007-03-02 | 2009-09-01 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
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WO2008109506A1 WO2008109506A1 (en) | 2008-09-12 |
WO2008109506B1 true WO2008109506B1 (en) | 2008-12-18 |
WO2008109506A9 WO2008109506A9 (en) | 2009-02-19 |
WO2008109506A8 WO2008109506A8 (en) | 2009-07-16 |
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JP5876637B2 (en) | 2006-10-18 | 2016-03-02 | マリーナ バイオテック,インコーポレイテッド | Nicked or gapped nucleic acid molecules and their use |
GB0720976D0 (en) * | 2007-10-26 | 2007-12-05 | Medical Res Council | Treatment of inflammatory disease |
JP2015507924A (en) * | 2012-02-08 | 2015-03-16 | アイシス ファーマシューティカルズ, インコーポレーテッド | Methods and compositions for modulating the expression of factor VII |
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AUPS078002A0 (en) * | 2002-02-27 | 2002-03-21 | Unisearch Limited | Dnazyme therapeutics |
US20060247193A1 (en) * | 2003-02-10 | 2006-11-02 | National Institute Of Advanced Industrial Science And Technology | Regulation of gene expression by dna interference |
CA2518475C (en) * | 2003-03-07 | 2014-12-23 | Alnylam Pharmaceuticals, Inc. | Irna agents comprising asymmetrical modifications |
JP2009514877A (en) * | 2005-11-04 | 2009-04-09 | エムディーアールエヌエー,インコーポレイテッド | Peptide-Dither substrate RNA conjugates as siRNA delivery vehicles |
AU2007229161B2 (en) * | 2006-03-23 | 2012-07-12 | Roche Innovation Center Copenhagen A/S | Small internally segmented interfering RNA |
JP5876637B2 (en) * | 2006-10-18 | 2016-03-02 | マリーナ バイオテック,インコーポレイテッド | Nicked or gapped nucleic acid molecules and their use |
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WO2008109506A1 (en) | 2008-09-12 |
WO2008109506A9 (en) | 2009-02-19 |
WO2008109506A8 (en) | 2009-07-16 |
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