WO2008109498A4 - Nucleic acid compounds for inhibiting hdac gene expression and uses thereof - Google Patents
Nucleic acid compounds for inhibiting hdac gene expression and uses thereof Download PDFInfo
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- WO2008109498A4 WO2008109498A4 PCT/US2008/055612 US2008055612W WO2008109498A4 WO 2008109498 A4 WO2008109498 A4 WO 2008109498A4 US 2008055612 W US2008055612 W US 2008055612W WO 2008109498 A4 WO2008109498 A4 WO 2008109498A4
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- 230000014509 gene expression Effects 0.000 title claims abstract 12
- 102000039446 nucleic acids Human genes 0.000 title claims abstract 5
- 108020004707 nucleic acids Proteins 0.000 title claims abstract 5
- -1 Nucleic acid compounds Chemical class 0.000 title claims 7
- 230000002401 inhibitory effect Effects 0.000 title 1
- 108020004999 messenger RNA Proteins 0.000 claims abstract 60
- 150000007523 nucleic acids Chemical class 0.000 claims abstract 26
- 102100039996 Histone deacetylase 1 Human genes 0.000 claims abstract 24
- 101001032113 Homo sapiens Histone deacetylase 7 Proteins 0.000 claims abstract 16
- 230000000295 complement effect Effects 0.000 claims abstract 13
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract 12
- 102100038720 Histone deacetylase 9 Human genes 0.000 claims abstract 11
- 102100038715 Histone deacetylase 8 Human genes 0.000 claims abstract 10
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract 9
- 102100038719 Histone deacetylase 7 Human genes 0.000 claims abstract 9
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 claims abstract 9
- 101000899259 Homo sapiens Histone deacetylase 4 Proteins 0.000 claims abstract 9
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 claims abstract 9
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 claims abstract 9
- 101001032118 Homo sapiens Histone deacetylase 8 Proteins 0.000 claims abstract 9
- 101001032092 Homo sapiens Histone deacetylase 9 Proteins 0.000 claims abstract 9
- 102100021455 Histone deacetylase 3 Human genes 0.000 claims abstract 8
- 102100039999 Histone deacetylase 2 Human genes 0.000 claims abstract 7
- 102100021454 Histone deacetylase 4 Human genes 0.000 claims abstract 7
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 claims abstract 7
- 101001035694 Homo sapiens Polyamine deacetylase HDAC10 Proteins 0.000 claims abstract 7
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims abstract 6
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 claims abstract 6
- 238000000034 method Methods 0.000 claims abstract 5
- 238000012986 modification Methods 0.000 claims abstract 5
- 230000004048 modification Effects 0.000 claims abstract 5
- 239000002777 nucleoside Substances 0.000 claims abstract 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims abstract 3
- 229920002477 rna polymer Polymers 0.000 claims abstract 3
- 239000002773 nucleotide Substances 0.000 claims 25
- 125000003729 nucleotide group Chemical group 0.000 claims 25
- 108010024124 Histone Deacetylase 1 Proteins 0.000 claims 22
- 108091028043 Nucleic acid sequence Proteins 0.000 claims 22
- 108010074724 histone deacetylase 3 Proteins 0.000 claims 13
- 101710177326 Histone deacetylase 9 Proteins 0.000 claims 9
- 102000011427 Histone Deacetylase 6 Human genes 0.000 claims 8
- 108010023925 Histone Deacetylase 6 Proteins 0.000 claims 8
- 101710177327 Histone deacetylase 8 Proteins 0.000 claims 8
- 102000016182 Histone deacetylase 5 Human genes 0.000 claims 7
- 108050004676 Histone deacetylase 5 Proteins 0.000 claims 7
- 102000047036 human HDAC2 Human genes 0.000 claims 7
- 102000050246 human HDAC4 Human genes 0.000 claims 7
- 102000048596 human HDAC5 Human genes 0.000 claims 7
- 102000054908 human HDAC6 Human genes 0.000 claims 7
- 102000045911 human HDAC7 Human genes 0.000 claims 7
- 102000054168 human HDAC8 Human genes 0.000 claims 7
- 102000048719 human HDAC9 Human genes 0.000 claims 7
- 125000000217 alkyl group Chemical group 0.000 claims 6
- 210000004027 cell Anatomy 0.000 claims 6
- YHRRPHCORALGKQ-FDDDBJFASA-N 2'-O-methyl-5-methyluridine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C)=C1 YHRRPHCORALGKQ-FDDDBJFASA-N 0.000 claims 5
- SNNBPMAXGYBMHM-JXOAFFINSA-N 5-methyl-2-thiouridine Chemical compound S=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SNNBPMAXGYBMHM-JXOAFFINSA-N 0.000 claims 5
- 108010023981 Histone Deacetylase 2 Proteins 0.000 claims 5
- 101710177324 Histone deacetylase 4 Proteins 0.000 claims 5
- 101001035703 Homo sapiens Histone deacetylase 11 Proteins 0.000 claims 5
- 102000045898 human HDAC1 Human genes 0.000 claims 5
- 102000043892 human HDAC10 Human genes 0.000 claims 5
- 102000053348 human HDAC11 Human genes 0.000 claims 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 101150084750 1 gene Proteins 0.000 claims 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims 4
- 229910019142 PO4 Inorganic materials 0.000 claims 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 3
- 239000010452 phosphate Substances 0.000 claims 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 2
- 125000003342 alkenyl group Chemical group 0.000 claims 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 2
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 125000004103 aminoalkyl group Chemical group 0.000 claims 2
- 238000000137 annealing Methods 0.000 claims 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims 2
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims 2
- 125000001188 haloalkyl group Chemical group 0.000 claims 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- 210000005260 human cell Anatomy 0.000 claims 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 2
- 230000003463 hyperproliferative effect Effects 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 125000005647 linker group Chemical group 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 239000002718 pyrimidine nucleoside Substances 0.000 claims 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 108091005772 HDAC11 Proteins 0.000 abstract 2
- 102100039385 Histone deacetylase 11 Human genes 0.000 abstract 2
- 102100021453 Histone deacetylase 5 Human genes 0.000 abstract 2
- 102100022537 Histone deacetylase 6 Human genes 0.000 abstract 2
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 abstract 2
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 abstract 2
- 102100039388 Polyamine deacetylase HDAC10 Human genes 0.000 abstract 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 abstract 2
- 230000003247 decreasing effect Effects 0.000 abstract 2
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 230000030279 gene silencing Effects 0.000 abstract 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 abstract 1
- 229940045145 uridine Drugs 0.000 abstract 1
- 0 CC(N(C(*C(C*)C1*)C1*=C)C=C(*)C(C)=O)=* Chemical compound CC(N(C(*C(C*)C1*)C1*=C)C=C(*)C(C)=O)=* 0.000 description 2
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- 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
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Abstract
The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing HDAC (e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAC10, HDAC11) 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 an HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAC10, or HDAC11 1 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 an HDAC gene in a cell or in a subject to treat an HDAC-related disease.
Claims
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human histone deacetylase (HDAC) 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 a human histone deacetylase 1 (HDACl) mRNA as set forth in SEQ ID NO: 1158; human histone deacetylase 2 (HD AC2) mRNA as set forth in SEQ ID NO: 1364; human histone deacetylase 3 (HD AC3) mRNA as set forth in SEQ ID NO:2009; human histone deacetylase 4 (HD AC4) mRNA as set forth in SEQ ID NO:2199; human histone deacetylase 5 (HD AC5) mRNA as set forth in SEQ ID NO:3074 or 3075; human histone deacetylase 6 (HDAC6) mRNA as set forth in SEQ ID NO: 4077; human histone deacetylase 7A(HDAC7A) mRNA as set forth in SEQ ID NO:4477, 4478, 4479, or 4480; human histone deacetylase 8 (HDAC8) mRNA as set forth in SEQ ID NO:5782; human histone deacetylase 9 (HDAC9) mRNA as set forth in SEQ ID NO:5949, 5950, 5951, 5952, or 5953; human histone deacetylase 10 (HDAClO) mRNA as set forth in SEQ ID NO:7363; or human histone deacetylase 11 (HDACl 1) mRNA as set forth in SEQ ID NO:7625, 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 HDAC 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 a human histone deacetylase 1 (HDACl) mRNA as set forth in SEQ ID NO: 1158; human histone deacetylase 2 (HDAC2) mRNA as set forth in SEQ ID NO: 1364; human histone deacetylase 3 (HDAC3) mRNA as set forth in SEQ ID NO:2009; human histone deacetylase 4 (HD AC4) mRNA as set forth in SEQ ID NO:2199; human histone deacetylase 5 (HDAC5) mRNA as set forth in SEQ ID NO:3074 or 3075; human histone deacetylase 6 (HDAC6) mRNA as set forth in SEQ ID NO: 4077; human histone deacetylase 7A(HDAC7A) mRNA as set forth in SEQ ID NO:4477, 4478, 4479, or 4480; human histone deacetylase 8 (HDAC8) mRNA as set forth in SEQ ID NO:5782; human histone deacetylase 9 (HDAC9) mRNA as set forth in SEQ ID NO:5949, 5950, 5951, 5952, or 5953; human histone deacetylase 10 (HDAClO) mRNA as set forth in SEQ ID NO:7363; or human histone deacetylase 11 (HDACl 1) mRNA as set forth in SEQ ID NO:7625, 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 nucleoside according to Formula
wherein: 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-C]0 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.
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 a human HDAC niRNA, the mdRNA molecule comprising a first strand that is complementary to a portion of any one of a human histone deacetylase 1 (HDACl) mRNA as set forth in SEQ ID NO: 1158; human histone deacetylase 2 (HD AC2) mRNA as set forth in SEQ ID NO: 1364; human histone deacetylase 3 (HD AC3) mRNA as set forth in SEQ ID NO:2009; human histone deacetylase 4 (HDAC4) mRNA as set forth in SEQ ID NO:2199; human histone deacetylase 5 (HDAC5) mRNA as set forth in SEQ ID NO: 3074 or 3075; human histone deacetylase 6 (HD AC6) mRNA as set forth in SEQ ID NO: 4077; human histone deacetylase 7A(HD AC7 A) mRNA as set forth in SEQ ID NO:4477, 4478, 4479, or 4480; human histone deacetylase 8 (HDAC8) mRNA as set forth in SEQ ID NO:5782; human histone deacetylase 9 (HDAC9) mRNA as set forth in SEQ ID NO:5949, 5950, 5951, 5952, or 5953; human histone deacetylase 10 (HDAClO) mRNA as set forth in SEQ ID NO: 7363; or human histone deacetylase 11 (HDACl 1) mRNA as set forth in SEQ ID NO:7625, 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.
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human HDACl nucleic acid sequence as set forth in any one of SEQ ID NOS:1 159-1363, or human HDAC2 nucleic acid sequence as set forth in any one of SEQ ID NOS: 1365-2008, or human HDAC3 nucleic acid sequence as set forth in any one of SEQ ID NOS :2010-2198, or human HDAC4 nucleic acid sequence as set forth in any one of SEQ ID NOS:2200- 3073, or human HDAC5 nucleic acid sequence as set forth in any one of SEQ ID NOS: 3076-4076, or human HDAC6 nucleic acid sequence as set forth in any one of SEQ ID NOS:4078-4476, or human HDAC7A nucleic acid sequence as set forth in any one of SEQ ID NOS:3490, 4481-5781, or human HDAC8 nucleic acid sequence as set forth in any one of SEQ ID NOS:5783-5948, or human HDAC9 nucleic acid sequence as set forth in any one of SEQ ID NOS:5954-7362, or human HDAClO nucleic acid sequence as set forth in any one of SEQ ID NOS:7364-7624, or human HDACl 1 nucleic acid sequence as set forth in any one of SEQ ID NOS:7626-7791.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human HDACl nucleic acid sequence as set forth in any one of SEQ ID NOS: 1159-1363, or human HDAC2 nucleic acid sequence as set forth in any one of SEQ ID NOS:1365-2008, or human HDAC3 nucleic acid sequence as set forth in any one of SEQ ID NOS:2010-2198, or human HDAC4 nucleic acid sequence as set forth in any one of SEQ ID NOS:2200- 3073, or human HDAC5 nucleic acid sequence as set forth in any one of SEQ ID NOS:3076-4076, or human HDAC6 nucleic acid sequence as set forth in any one of SEQ ID NOS:4078-4476, or human HDAC7A nucleic acid sequence as set forth in any one of SEQ ID NOS:3490, 4481-5781, or human HDAC8 nucleic acid sequence as set forth in any one of SEQ ID NOS:5783-5948, or human HDAC9 nucleic acid sequence as set forth in any one of SEQ ID NOS:5954-7362, or human HDAClO nucleic acid sequence as set forth in any one of SEQ ID NOS:7364-7624, or human HDACl 1 nucleic acid sequence as set forth in any one of SEQ ID NOS:7626-7791.
21. A method for reducing the expression of a human HDAC gene, comprising administering an mdRNA molecule according to any one of claims 1-22 to a cell expressing a human HDACl, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAClO, or HDACl 1 gene, wherein the mdRNA molecule reduces expression of the HDACl, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAClO, or HDACl 1 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 histone deacetylase (HDAC) 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 a human histone deacetylase 1 (HDACl) mRNA as set forth in SEQ ID NO: 1158; human histone deacetylase 2 (HD AC2) mRNA as set forth in SEQ ID NO: 1364; human histone deacetylase 3 (HD AC3) mRNA as set forth in SEQ ID NO:2009; human histone deacetylase 4 (HD AC4) mRNA as set forth in SEQ ID NO:2199; human histone deacetylase 5 (HD AC5) mRNA as set forth in SEQ ID NO:3074 or 3075; human histone deacetylase 6 (HDAC6) mRNA as set forth in SEQ ID NO: 4077; human histone deacetylase 7A(HD AC7A) mRNA as set forth in SEQ ID NO:4477, 4478, 4479, or 4480; human histone deacetylase 8 (HDAC8) mRNA as set forth in SEQ ID NO:5782; human histone deacetylase 9 (HDAC9) mRNA as set forth in SEQ ID NO:5949, 5950, 5951, 5952, or 5953; human histone deacetylase 10 (HDAClO) mRNA as set forth in SEQ ID NO: 7363; or human histone deacetylase 11 (HDACl 1) mRNA as set forth in SEQ ID NO: 7625, 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 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 HDAC 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 a human histone deacetylase 1 (HDACl) mRNA as set forth in SEQ ID NO: 1158; human histone deacetylase 2 (HD AC2) mRNA as set forth in SEQ ID NO: 1364; human histone deacetylase 3 (HDAC3) mRNA as set forth in SEQ ID NO:2009; human histone deacetylase 4 (HD AC4) mRNA as set forth in SEQ ID NO:2199; human histone deacetylase 5 (HDAC5) mRNA as set forth in SEQ ID NO:3074 or 3075; human histone deacetylase 6 (HDAC6) mRNA as set forth in SEQ ID NO: 4077; human histone deacetylase 7A(HDAC7A) mRNA as set forth in SEQ ID NO:4477, 4478, 4479, or 4480; human histone deacetylase 8 (HD AC8) mRNA as set forth in SEQ ID NO:5782; human histone deacetylase 9 (HDAC9) mRNA as set forth in SEQ ID NO:5949, 5950, 5951, 5952, or 5953; human histone deacetylase 10 (HDAClO) mRNA as set forth in SEQ ID NO:7363; or human histone deacetylase 11 (HDACl 1) mRNA as set forth in SEQ ID NO:7625, 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:
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'-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 HDAC gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing a HDACl, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAClO, or HDACl 1 gene, wherein the mdRNA molecule reduces expression of the HDACl, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7A, HDAC8, HDAC9, HDAClO, or HDACl 1 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.
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| 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 |
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| AU2009212920A Division AU2009212920A1 (en) | 2007-03-02 | 2009-09-01 | Nucleic acid compounds for inhibiting gene expression and uses thereof |
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| WO2010056677A1 (en) * | 2008-11-12 | 2010-05-20 | Duke University | Methods of inhibiting cancer cell growth with hdac inhibitors and methods of screening for hdac10 inhibitors |
| EP3099811B1 (en) * | 2014-01-28 | 2018-09-12 | Qiagen GmbH | Method of amplification of a short tandem repeat locus |
| CN111840311B (en) * | 2020-07-31 | 2021-11-12 | 上海交通大学医学院附属第九人民医院 | Use of siRNA molecule composition for preparing medicament for inhibiting scar formation against HDAC5 |
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| US20060148743A1 (en) * | 2001-05-18 | 2006-07-06 | Vasant Jadhav | RNA interference mediated inhibition of histone deacetylase (HDAC) gene expression using short interfering nucleic acid (siNA) |
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