WO2008109371B1 - Nucleic acid compounds for inhibiting p38 mapk family gene expression and uses thereof - Google Patents
Nucleic acid compounds for inhibiting p38 mapk family gene expression and uses thereofInfo
- Publication number
- WO2008109371B1 WO2008109371B1 PCT/US2008/055373 US2008055373W WO2008109371B1 WO 2008109371 B1 WO2008109371 B1 WO 2008109371B1 US 2008055373 W US2008055373 W US 2008055373W WO 2008109371 B1 WO2008109371 B1 WO 2008109371B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- strand
- molecule
- seq
- mdrna
- human
- Prior art date
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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 one or more p38 MAPK family 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 one or more p38 MAPK family mRNA. In addition, the meroduplex mayhave at least one uridine is a 5-methyluridine, a nucleoside is a locked nucleic acid, andoptionally other modifications, or any combination thereof. Also provided are methods of decreasing expression of one or more p38 MAPK family gene in a cell or in a subject to treat one or more p38 MAPK family-related disease.
Claims
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of one or more human p38 mitogen-activated protein kinase (MAPK) family mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the one or more human p38 MAPK family mRNA as set forth in SEQ ID NO:1161, 1162, 1163, or 1164 and is fully complementary with up to three mismatches to at least one other human p38 MAPK family mRNA selected from SEQ ID NO:1158, 1159, or 1160, 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. The mdRNA molecule of claim 1 wherein the first strand is complementary to SEQ ID NOS:1158-1164> or SEQ IDNOS:1158 and 1161-1164, or SEQ ID NOS:1159 and 1161-1164, or SEQ ID NOS:1160 and 1161-1164, or SEQ ID NOS:1158, 1159, and 116O5 or SEQ ID NOS:1158, 1159, and 1161-1164, or SEQ ID
89 NOS:1158, 1160, and 1161-U64, or SEQ ID NOS:1159-1164, or SEQ ID NOS:1158 and 1159, or SEQ IDNOS:1158 and 1160, or SEQ ID NOS:1159 and 1160.
8. An mdRNA molecule that down regulates the expression of one or more human ρ38 MAPK family mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the one or more human ρ38 MAPK family mRNA as set forth in SEQ ID NO: 1161 , 1162, 1163, or 1164 and is fully complementary with up to three mismatches to at least one other human p38 MAPK family mRNA selected from SEQ H) NO:1158, 1159, or 1160, 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 one pyrimidine of the mdRNA molecule is a pyrimidine nucleosideaccording to Formula I or II:
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted Ci-Cjo alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, halσalkyl, trifluorornethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-CiO 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,
90 R3 and R4 are each independently a hydroxy., a protected hydroxyl, a phosphate, or an internucleoside linking group, and R5 and R8 are each independently O or S.
9. The mdRNA molecule of claim 8 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
10. The mdRNA molecule of claim 8 wherein the gap comprises from 1 to 10 unpaired nucleotides.
11. The mdRNA molecule of claim 8 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
12. The mdRNA molecule of claim 8 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'-O-allyl, and fluoro.
13. The mdRNA molecule of claim 8 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
14. The mdRNA molecule of claim 8 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.
15. The mdRNA molecule of claim 8 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.
16. The mdRNA molecule of claim 8 wherein the first strand is complementary to SEQ ID NOS:1158-1164, or SEQ ID NOS:1158 and 1161-1164, or SEQ ID NOSrI 159 and 1161-1164, or SEQ ID NOS: 1160 and 1161-1164, or SEQ ID NOS:1158, 1159, and 1160, or SEQ ID NOS:1158, 1159, and 1161-1164, or SEQ ID NOS:1158, 1160, and 1161-1164, or SEQ IDNOSrI 159-1164, or SEQ ID NOS: 1158 and 1159, or SEQ ID NOSrI 158 and 1160, or SEQ ID NOS:1159 and 1160.
91
17. An mdRNA molecule that down regulates the expression of a human p38 MAPK family mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human p38 MAPK family mRNA as setforth in SEQ ID NO:1161, 1162, 1163, or 1164 and is fully complementary with up to three mismatches to at least one other human p38 MAPK family mRNA selected from SEQ ID NO:1158, 1159, or 1160, 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.
18. The mdRNA molecule of claim 17 wherein the first strand is 15 to 25 nucleotides in length or 26 to 40 nucleotides in length.
19. The mdRNA molecule of claim 17 wherein the gap comprises from 1 to 10 unpaired nucleotides.
20. The mdRNA molecule of claim 17 wherein the mdRNA molecule comprises at least one S-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
21. The mdRNA molecule of claim 17 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human p38 MAPK family nucleic acid sequence as set forth in any one of SEQ ID NOS: 1165-2611.
22. The mdRNA molecule of claim 17 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human p38 MAPK family nucleic acid sequence as set forth in any one of SEQ ID NOS: 1165-2611.
23. A method for reducing the expression of one or more human p38 MAPK family genes, comprising administering an mdRNA molecule according to any one of claims 1-22 to a cell expressing one or more human p38 MAPK family genes, wherein the mdRNA molecule reduces the expression of the one or more human p38 MAPK family genes in the cell.
24. The method according to claim 23 wherein the cell is a human cell.
92
25. 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.
26. A double-stranded ribonucleic acid (dsRNA) molecule that down regulates the expression of one or more human p38 mitogen- activated protein kinase (MAPK) family mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to the one or more human p38 MAPK family mRNA as set forth in SEQ ID NO:1161, 1162, 1163, or 1164 and is fully complementary with up to three mismatches to at least one other human p38 MAPK family mRNA selected from SEQ ID NO: 1158, 1159, or 1160, 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.
27. The dsRNA molecule of claim 26 wherein the first strand is from 27 to 35 nucleotides in length.
28. The dsRNA molecule of claim 26 wherein the dsRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidine, or 2'-O-methyl-5- methyluridine.
29. The dsRNA molecule of claim 26 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,
30. The dsRNA molecule of claim 26 wherein the 3r-overhang has from one to four nucleotides and is on the first strand.
31. The dsRNA molecule of claim 26 wherein the dsRNA molecule has a 5'-terminal end comprising a hydroxyl or a phosphate.
32. A dsRNA molecule that down regulates the expression of one or more human p38 MAPK family mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to the one or more human p38 MAPK family mRNA as set forth in SEQ ID NO: 1161, 1162, 1163, or 1164 and is
93 fully complementary with up to three mismatches to at least one other human p38 MAPK. family mRNA selected from. SEQ ID NO: 1158, 1159, or 1160, 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:
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3. -OCH2CH2OCH3, halogen, substituted or unsubstituted C1-CiO alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, diaϊkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-Cio alkenyl, substituted or unsubstituted -O-allyl, -0-CHaCH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-CiO alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C=N5 or heterαcyclo group,
R3 and R4 are each independently ahydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and
Rs and R8 are each independently O or S.
33. The dsRNA molecule of claim 32 wherein the first strand is from 27 to 35 nucleotides in length.
34. The dsRNA molecule of claim 32 wherein at least one nucleoside is according to Formula I and in which R1 is methyl and R2 is -OH or -O-methyl.
94
35. The dsRNA molecule of claim 32 wherein at least one R2 is selected from the group consisting of 2'-0-(Ci-C5) alkyl, 2'-O-methyl, 2'-OCH2OCHsCH3, 2'-OCH2CH2OCH3, 2'-O-allyl, and 2'-fhioro.
36. The dsRNA molecule of claim 32 wherein the dsRNA molecule comprises at least one 5 -metiiy .uridine, 2-thioribothymidine. or 2'-O-methyl-5- methyluridine.
37. The dsRNA molecule of claim 32 wherein the dsRNA molecule comprises at least one LNA, deoxy nucleotide, G clamp, 2f-sugar modification, modified internucleoside linkage, or any combination thereof.
38. The dsRNA molecule of claim 32, wherein the 3'-overhang has from one to four nucleotides and is on the first strand.
39. A method for reducing the expression of one or more human p38 MAPK family genes, comprising administering a dsRNA molecule according to any one of claims 26-38 to a cell expressing one or more human p38 MAPK family genes, wherein the dsRNA molecule reduces the expression of the one or more human ρ38 MAPK family genes in the cell,
40. The method according to claim 39 wherein the cell is a human cell.
41. Use of a dsRNA molecule as defined in any one of claims 26-40 for the manufacture of a medicament for use in the therapy of a hyperproliferative or inflammatory disease.
95
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 (14)
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 | ||
US95219107P | 2007-07-26 | 2007-07-26 | |
US95219207P | 2007-07-26 | 2007-07-26 | |
US95218807P | 2007-07-26 | 2007-07-26 | |
US60/952,188 | 2007-07-26 | ||
US60/952,192 | 2007-07-26 | ||
US60/952,191 | 2007-07-26 | ||
US95249907P | 2007-07-27 | 2007-07-27 | |
US60/952,499 | 2007-07-27 | ||
US95387307P | 2007-08-03 | 2007-08-03 | |
US60/953,873 | 2007-08-03 |
Related Parent Applications (1)
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PCT/US2008/055385 Continuation-In-Part WO2008109381A2 (en) | 2007-03-02 | 2008-02-28 | Nucleic acid compounds for inhibiting hif1a gene expression and uses thereof |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2008/055376 Continuation-In-Part WO2008109374A1 (en) | 2007-03-02 | 2008-02-28 | Nucleic acid compounds for inhibiting mapk 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 |
AU2009212920A Division AU2009212920A1 (en) | 2007-03-02 | 2009-09-01 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
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WO2008109371A1 WO2008109371A1 (en) | 2008-09-12 |
WO2008109371B1 true WO2008109371B1 (en) | 2008-11-13 |
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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 |
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AU2003216255A1 (en) * | 2002-02-20 | 2003-09-09 | Ribozyme Pharmaceuticals, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF MDR P-GLYCOPROTEIN GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
EP1942943A2 (en) * | 2005-11-04 | 2008-07-16 | Nastech Pharmaceutical Company Inc. | Peptide-dicer substrate rna conjugates as delivery vehicles for sirna |
DK2002004T3 (en) * | 2006-03-23 | 2015-11-30 | Roche Innovation Ct Copenhagen As | LITTLE INTERNAL SEGMENTED INTERFERENCE 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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