WO2008109358B1 - Nucleic acid compounds for inhibiting mapk1 gene expression and uses thereof - Google Patents
Nucleic acid compounds for inhibiting mapk1 gene expression and uses thereofInfo
- Publication number
- WO2008109358B1 WO2008109358B1 PCT/US2008/055356 US2008055356W WO2008109358B1 WO 2008109358 B1 WO2008109358 B1 WO 2008109358B1 US 2008055356 W US2008055356 W US 2008055356W WO 2008109358 B1 WO2008109358 B1 WO 2008109358B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- strand
- molecule
- mdrna
- nucleotides
- mapkl
- Prior art date
Links
- 0 *C(C1*)C(CO)*C1N(C=C(*)C(N)=C1)C1=* Chemical compound *C(C1*)C(CO)*C1N(C=C(*)C(N)=C1)C1=* 0.000 description 1
Classifications
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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
- C12N15/1137—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 enzymes
-
- 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.
Abstract
The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing MAPKl 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 MAPKl mRNA. In addition, the meroduplex may have at least one uridine is a 5-methyluridine, a nucleoside is a locked nucleic acid, or optionally other modifications, and any combination thereof. Also provided are methods of decreasing expression of a MAPKl gene in a cell or in a subject to treat a MAPKl -related disease.
Claims
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human mitogen-activated protein kinase 1 (MAPKl) mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of the human MAPKl mRNA as set forth in SEQ ID NO: 1158 or 1159, 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 a human MAPKl mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of the human MAPKl mRNA as set forth in SEQ ID NO: 1158 or 1159, 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 at least
82 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 C1-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-Ci0 alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡, 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.
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.
83
11. The mdRNA molecule of claim 7 wherein at least one R2 is selected from the group consisting of 2'-0-(C1-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 a human MAPKl mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of the human MAPKl mRNA as set forth in SEQ ID NO: 1158 or 1159, 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.
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.
84
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human MAPKl nucleic acid sequence as set forth in any one of SEQ ID NOS: 1160-1749.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human MAPKl nucleic acid sequence as set forth in any one of SEQ ID NOS: 1160-1749.
21. A method for reducing the expression of a human MAPK 1 gene, comprising administering an mdRNA molecule according to any one of claims 1-20 to a cell expressing the human MAPKl gene, wherein the mdRNA molecule reduces the expression of the human MAPKl 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 a human mitogen-activated protein kinase 1 (MAPKl) mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human MAPKl mRNA as set forth in SEQ ID NO: 1158 or 1159, 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.
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
85 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 a human MAPKl mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human MAPKl mRNA as set forth in SEQ ID NO: 1158 or 1159, 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:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted C1-C10 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-C10 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
86 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'-0-(Ci-C5) 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 MAPKl gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing the human MAPKl gene, wherein the dsRNA molecule reduces the expression of the human MAPKl 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.
87
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 | ||
US97187407P | 2007-09-12 | 2007-09-12 | |
US60/971,874 | 2007-09-12 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2008/055366 Continuation-In-Part WO2008109365A1 (en) | 2007-03-02 | 2008-02-28 | Nucleic acid compounds for inhibiting raf1 gene expression and uses thereof |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2008/055350 Continuation-In-Part WO2008109356A1 (en) | 2007-03-02 | 2008-02-28 | Nucleic acid compounds for inhibiting tnfsf13b gene expression and uses thereof |
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 |
Publications (2)
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WO2008109358A1 WO2008109358A1 (en) | 2008-09-12 |
WO2008109358B1 true WO2008109358B1 (en) | 2008-12-18 |
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PCT/US2008/055356 WO2008109358A1 (en) | 2007-03-02 | 2008-02-28 | Nucleic acid compounds for inhibiting mapk1 gene expression and uses thereof |
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Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9074205B2 (en) | 2006-10-18 | 2015-07-07 | Marina Biotech, Inc. | Nicked or gapped nucleic acid molecules and uses thereof |
WO2009151620A2 (en) * | 2008-06-13 | 2009-12-17 | Cornell Research Foundation, Inc. Wmc | Pain treatment using erk2 inhibitors |
WO2012021383A2 (en) * | 2010-08-10 | 2012-02-16 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF MITOGEN-ACTIVATED PROTEIN KINASE 1 (MAPK1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2003072590A1 (en) * | 2002-02-20 | 2003-09-04 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase genes |
WO2004097020A2 (en) * | 2003-04-25 | 2004-11-11 | Sirna Therapeutics, Inc. | Rna interference mediated inhibition of map kinase gene expression |
FR2864960A1 (en) * | 2004-01-14 | 2005-07-15 | Univ Rennes | Double-stranded interfering RNA, and vectors containing it, useful for treatment of cancer, modulate expression of the ERK2 protein and thus cell proliferation |
EP1942943A2 (en) * | 2005-11-04 | 2008-07-16 | Nastech Pharmaceutical Company Inc. | Peptide-dicer substrate rna conjugates as delivery vehicles for sirna |
WO2007107162A2 (en) * | 2006-03-23 | 2007-09-27 | Santaris Pharma A/S | Small internally segmented interfering rna |
US9074205B2 (en) * | 2006-10-18 | 2015-07-07 | Marina Biotech, Inc. | Nicked or gapped nucleic acid molecules and uses thereof |
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