WO2008109366A4 - Nucleic acid compounds for inhibiting ccnd1 gene expression and uses thereof - Google Patents

Nucleic acid compounds for inhibiting ccnd1 gene expression and uses thereof Download PDF

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Publication number
WO2008109366A4
WO2008109366A4 PCT/US2008/055368 US2008055368W WO2008109366A4 WO 2008109366 A4 WO2008109366 A4 WO 2008109366A4 US 2008055368 W US2008055368 W US 2008055368W WO 2008109366 A4 WO2008109366 A4 WO 2008109366A4
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Prior art keywords
strand
molecule
mdrna
nucleotides
human
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PCT/US2008/055368
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French (fr)
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WO2008109366A2 (en
WO2008109366A3 (en
Inventor
Steven C Quay
James Mcswiggen
Narendra K Vaish
Mohammad Ahmadian
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Mdrna Inc
Steven C Quay
James Mcswiggen
Narendra K Vaish
Mohammad Ahmadian
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Application filed by Mdrna Inc, Steven C Quay, James Mcswiggen, Narendra K Vaish, Mohammad Ahmadian filed Critical Mdrna Inc
Publication of WO2008109366A2 publication Critical patent/WO2008109366A2/en
Publication of WO2008109366A3 publication Critical patent/WO2008109366A3/en
Publication of WO2008109366A4 publication Critical patent/WO2008109366A4/en
Priority to US12/552,082 priority Critical patent/US20100105134A1/en
Priority to US13/327,545 priority patent/US20130011922A1/en

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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
    • 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.
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • 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
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed

Abstract

The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing CCNDl 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 CCNDl mRNA. In addition, the meroduplex may have at least one uridine substituted with a 5-methyluridine, a nucleoside that is a locked nucleic acid, or optionally other modifications, and any combination thereof. Also provided are methods of decreasing expression of a CCND 1 gene in a cell or in a subject to treat a CCND 1 -related disease.

Claims

83AMENDED CLAIMS received by the International Bureau on November 20, 2008
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human cyclin Dl (CCNDl) mRNA, comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of the human CCNDl mRNA as set forth in SEQ ID NO: 1158, 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-methyiuridine, 2-thioribothymidine, or 2'-O-methyl-5- methymridine.
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 CCNDl rnRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human CCNDl mRNA as set forth in SEQ ID NO; 1158, 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 84
pyrimidine of the mdRNA molecule is a pyrimidine nucleoside according to Formula I or II:
wherein:
R1 and R2 are each independently a -H5 -OH, -OCH3, -OCH2OCH2CH3. -OCH2CH2OCH3, halogen, substituted or unsubstituted C1-C10 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkyl aminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-CJO alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -O-CH=CHCH3» substituted or unsubstituted Ca-C1O alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -Cs, or heterocyclo group,
R3 and R4 are each independently a hydroxy!, a protected hydroxyl. a phosphate, or an inteπxucleoside 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. 85
11. The tndRNA 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'-O-allyl, and fluoro.
12. The mdRNA molecule of claim 7 wherein the mdRNA molecule comprises at least one 5-methyluridine, 2-thioribothymidrne, 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 rndRNA molecule that down regulates the expression of a human CCNDl mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human CCND 1 mRNA as set forth in SEQ ID NO: 1158, 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-thioribothymidine5 or 2'-O-methyl-5- methyluridme. 86
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length and is complementary to a human CCNDl nucleic acid sequence as set forth in any one of SEQ ID NOS:1159-1573.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human CCNDl nucleic acid sequence as set forth in any one of SEQ ID NOS: 1159-1573.
21. A method for reducing the expression of a human CCNDl gene, comprising administering an mdRNA molecule according to any one of claims 1 -20 to a cell expressing a human CCNDl gene, wherein the mdRNA molecule reduces the expression of the human CCNDl 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 cyclin Dl (CCNDl) mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human CCNDl mRNA as set forth in SEQ ID NO: 1158, 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-mefhyluridine, 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 87
clamp, 2'-sugar modification, modified internxjcleoside 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 a human CCNDl mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human CCNDl mRNA as set forth in SEQ ID NO: 1158, 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:
Figure imgf000007_0001
wherein:
R1 and R2 are each independently a -H5 -OH, -OCH3, -OCH2OCH2CH35 -OCH2CH2OCH3,, halogen, substituted or unsubstituted Ci-Cio alkyl, alkoxy. alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylarninoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted Cz-C1O 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. 88
R3 and R4 are each independently a hydroxyl, a protected hydroxyl, a phosphate, or an internucleoside linking group, and R3 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'-O-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 CCNDl gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing a human CCNDl gene, wherein the dsRNA molecule reduces the expression of the human CCNDl 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.
PCT/US2008/055368 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting ccnd1 gene expression and uses thereof WO2008109366A2 (en)

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
US1398207P 2007-12-14 2007-12-14
US61/013,982 2007-12-14

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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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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
DE102008033175A1 (en) 2008-07-15 2010-01-21 Merck Patent Gmbh Silica nanoparticles and their use for vaccination
CN110536964A (en) * 2017-03-10 2019-12-03 国立研究开发法人国立成育医疗研究中心 Antisense oligonucleotides and the prevention of glycogen storage disease Ia type or therapeutic composition
KR20210130854A (en) 2018-03-09 2021-11-01 다이이찌 산쿄 가부시키가이샤 Therapeutic agent for glycogen storage disease type ia

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US8329888B2 (en) * 2006-03-23 2012-12-11 Santaris Pharma 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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