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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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.
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 |
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| 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 | ||
| US1240407P | 2007-12-07 | 2007-12-07 | |
| US61/012,404 | 2007-12-07 |
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| PCT/US2008/055622 Continuation-In-Part WO2008109503A1 (en) | 2007-03-02 | 2008-03-03 | Nucleic acid compounds for inhibiting ms4a1 gene expression and uses thereof |
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| PCT/US2008/055563 Continuation-In-Part WO2008109475A1 (en) | 2007-03-02 | 2008-02-29 | Nucleic acid compounds for inhibiting sirt2 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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| WO2008109498A4 true WO2008109498A4 (en) | 2009-04-30 |
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| WO2008049078A1 (en) | 2006-10-18 | 2008-04-24 | Nastech Pharmaceutical Company Inc. | Nicked or gapped nucleic acid molecules and uses thereof |
| US8664182B2 (en) | 2008-11-12 | 2014-03-04 | 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) |
| WO2008030239A1 (en) * | 2006-09-05 | 2008-03-13 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF HISTONE DEACETYLASE (HDAC) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| US20050136437A1 (en) * | 2003-08-25 | 2005-06-23 | Nastech Pharmaceutical Company Inc. | Nanoparticles for delivery of nucleic acids and stable double-stranded RNA |
| 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 |
| EP2002004B1 (en) * | 2006-03-23 | 2015-10-14 | Roche Innovation Center Copenhagen A/S | Small internally segmented interfering rna |
| WO2008049078A1 (en) * | 2006-10-18 | 2008-04-24 | Nastech Pharmaceutical Company Inc. | Nicked or gapped nucleic acid molecules and uses thereof |
-
2008
- 2008-03-03 WO PCT/US2008/055612 patent/WO2008109498A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008109498A2 (en) | 2008-09-12 |
| WO2008109498A3 (en) | 2009-03-12 |
| WO2008109498A8 (en) | 2009-12-10 |
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