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WO2008109548A4 - Nucleic acid compounds for inhibiting tgfb gene expression and uses thereof - Google Patents

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

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Publication number
WO2008109548A4
WO2008109548A4 PCT/US2008/055698 US2008055698W WO2008109548A4 WO 2008109548 A4 WO2008109548 A4 WO 2008109548A4 US 2008055698 W US2008055698 W US 2008055698W WO 2008109548 A4 WO2008109548 A4 WO 2008109548A4
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strand
molecule
human
mrna
mdrna
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WO2008109548A3 (en
WO2008109548A2 (en
Inventor
Steven C Quay
James Mcswiggen
Narendra K Vaish
Mohammad Ahmadian
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Marina Biotech Inc
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MDRNA Inc
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Publication of WO2008109548A4 publication Critical patent/WO2008109548A4/en
Priority to US12/552,082 priority Critical patent/US20100105134A1/en
Anticipated expiration legal-status Critical
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
    • C12N15/1136—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 growth factors, growth regulators, cytokines, lymphokines or hormones
    • 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 nucleic acids [NA]
    • 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

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  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • General Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing TGFBl, TGFB2, and/or TGFB3 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 TGFBl, TGFB2, and/or TGFB3 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 TGFB l, TGFB2, or TGFB3 gene in a cell or in a subject to treat a TGFBl-, TGFB2-, or TGFB3-related disease.

Claims

AMENDED CLAIMS received by the International Bureau on 02 Feb 2009 (02.02.2009)
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human transforming growth factor, beta-1 (TGFBl) mRNA, a human transforming growth factor, beta-2 (TGFB2) mRNA, and/or a human transforming growth factor, beta-3 (TGFB3) mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of a human TGFBl mRNA as set forth in SEQ ID NO: 1158, a human TGFB2 mRNA as set forth in SEQ ID NO: 1388, and/or a human TGFB3 mRNA as set forth in SEQ ID NO: 1555, 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 TGFBl mRNA, TGFB2 mRNA, and/or TGFB3 mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of a human TGFBl mRNA as set forth in SEQ ID NO: 1 158, a human TGFB2
86 niRNA as set forth in SEQ ID NO:1388, and/or a human TGFB3 mRNA as set forth in SEQ ID NO: 1555, 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 I or II:
Figure imgf000004_0001
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-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.
87
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-(C]-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 TGFBl mRNA, TGFB2 mRNA, and/or TGFB3 mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of a human TGFBl mRNA as set forth in SEQ ID NO: 1158, a human TGFB2 mRNA as set forth in SEQ ID NO: 1388, and/or a human TGFB3 mRNA as set forth in SEQ ID NO: 1555, 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.
88
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 TGFBl nucleic acid sequence as set forth in any one of SEQ ID NOS: 1 159-1387, a human TGFB2 nucleic acid sequence as set forth in any one of SEQ ID NOS: 1389-1554, or a human TGFB3 nucleic acid sequence as set forth in any one of SEQ ID NOS:1556-1805.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human TGFBl nucleic acid sequence as set forth in any one of SEQ ID NOS:1159-1387, a human TGFB2 nucleic acid sequence as set forth in any one of SEQ ID NOS: 1389-1554, or a human TGFB3 nucleic acid sequence as set forth in any one of SEQ ID NOS:1556-1805.
21. A method for reducing the expression of a human TGFB 1 , TGFB2, and/or TGFB3 gene, comprising administering an mdRNA molecule according to any one of claims 1-20 to a cell expressing the human TGFBl, TGFB2, and/or TGFB3 gene, wherein the mdRNA molecule reduces the expression of the human TGFBl, TGFB2, and/or TGFB3 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 transforming growth factor, beta-1 (TGFBl) mRNA, a human transforming growth factor, beta-2 (TGFB2) mRNA, and/or a human transforming growth factor, beta-3 (TGFB3) mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a
89 portion of a human TGFBl mRNA as set forth in SEQ ID NO: 1158, a human TGFB2 mRNA as set forth in SEQ ID NO: 1388, and/or a human TGFB3 mRNA as set forth in SEQ ID NO: 1555, 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 TGFBl mRNA, TGFB2 mRNA, and/or TGFB3 mRNA mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of a human TGFBl mRNA as set forth in SEQ ID NO: 1 158, a human TGFB2 mRNA as set forth in SEQ ID NO: 1388, and/or a human TGFB3 mRNA as set forth in SEQ ID NO: 1555, 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:
90
Figure imgf000008_0001
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-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 -0-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'-OCH2OCH2CH3j 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.
91
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 TGFB 1 , TGFB2, and/or TGFB3 gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing the TGFBl, TGFB2, and/or TGFB3 gene, wherein the dsRNA molecule reduces the expression of the TGFBl, TGFB2, and/or TGFB3 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.
92
PCT/US2008/055698 2007-03-02 2008-03-03 Nucleic acid compounds for inhibiting tgfb gene expression and uses thereof Ceased WO2008109548A2 (en)

Priority Applications (2)

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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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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
US1240207P 2007-12-07 2007-12-07
US61/012,402 2007-12-07

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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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CA2666657A1 (en) 2006-10-18 2008-04-24 Nastech Pharmaceutical Company Inc. Nicked or gapped nucleic acid molecules and uses thereof
US20110172296A1 (en) * 2010-01-12 2011-07-14 Bennett C Frank Modulation of transforming growth factor-beta 1 expression
AR083445A1 (en) 2010-10-14 2013-02-27 Univ Mie siRNA AGAINST FIBROSIS
EP3235906B1 (en) * 2014-12-15 2021-06-23 Bonac Corporation Single-stranded nucleic acid molecule for inhibiting tgf- beta 1 expression

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AU2003275474A1 (en) * 2002-10-07 2004-05-04 Isis Pharmaceuticals, Inc. Method for inhibiting angiogenesis with transforming growth factor-beta 3 inhibitors
KR20080066987A (en) * 2005-11-04 2008-07-17 나스텍 파마수티컬 컴퍼니 인코포레이티드 Peptide-Dicer Substrates RNA Conjugates as Delivery Carriers for SiRNA
US8329888B2 (en) * 2006-03-23 2012-12-11 Santaris Pharma A/S Small internally segmented interfering RNA
CA2666657A1 (en) * 2006-10-18 2008-04-24 Nastech Pharmaceutical Company Inc. Nicked or gapped nucleic acid molecules and uses thereof

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