WO2008109372A4 - Nucleic acid compounds for inhibiting pdgf gene expression and uses thereof - Google Patents

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

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WO2008109372A4
WO2008109372A4 PCT/US2008/055374 US2008055374W WO2008109372A4 WO 2008109372 A4 WO2008109372 A4 WO 2008109372A4 US 2008055374 W US2008055374 W US 2008055374W WO 2008109372 A4 WO2008109372 A4 WO 2008109372A4
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strand
molecule
human
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WO2008109372A2 (en
WO2008109372A3 (en
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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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Publication of WO2008109372A2 publication Critical patent/WO2008109372A2/en
Publication of WO2008109372A3 publication Critical patent/WO2008109372A3/en
Publication of WO2008109372A4 publication Critical patent/WO2008109372A4/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
    • C12N15/1138—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 receptors or cell surface proteins
    • 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.

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  • Engineering & Computer Science (AREA)
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  • Biomedical Technology (AREA)
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  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
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  • Wood Science & Technology (AREA)
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  • Physics & Mathematics (AREA)
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  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present disclosure provides meroduplex ribonucleic acid molecules (mdRNA) capable of decreasing or silencing PDGF 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 PDGF 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 a PDGF gene in a cell or in a subject to treat a PDGF -related disease.

Claims

AMENDED CLAIMS Received by the International Bureau on 11.Mar.2009 (11.03.2009)
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human platelet-derived growth factor (PDGF) mRNA, the mdKNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to any one of PDGFA mRNA as set form in SEQ ID NO: 1158 or 1159, human PDGFB mRNA as set forth in SEQ ID NO: 1544 or 1545, human PDGFC mRNA as set forth in SEQ ID NO:2104, or human PDGFD mRNA as set forth in SEQ ID NO:2396 or 2397, 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, 21 -sugar modification, modified intemucleoside 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 PDGF mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to any one of human PDGFA mRNA as set forth in SEQ ID NO: 1158 or 1159, human PDGFB mRNA as set forth in SEQ ID NO: 1544 or 1545, human PDGFC mRNA as set forth in SEQ ID NO.2104, or human PDGFD
85 mRNA as set forth in SEQ ID NO:2396 or 2397, 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
Figure imgf000004_0001
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted Ci-C10 alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-C 10 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-C 10 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
R3 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.
86
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.
1 1. 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'-O-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 intemucleoside 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 PDGF mRNA, the mdRNA molecule comprising a first strand that is complementary to any one of human PDGFA mRNA as set forth in SEQ ID NO: 1158 or 1159, human PDGFB mRNA as set forth in SEQ ID NO: 1544 or 1545, human PDGFC mRNA as set forth in SEQ ID NO.2104, or human PDGFD mRNA as set forth in SEQ ID NO:2396 or 2397, 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 i s 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.
87
18. The mdRN A molecule of claim 15 wherein the mdRN A 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 PDGFA nucleic acid sequence as set forth in any one of SEQ ID NOS: 1160-1380, or human PDGFB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1546-1864, human PDGFC nucleic acid sequence as set forth in any one of SEQ ID NOS :2105-2270, or human PDGFD nucleic acid sequence as set forth in any one of SEQ ID NOS.2398-2620.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human PDGFA nucleic acid sequence as set forth in any one of SEQ ID NOS:1381-1543, or human PDGFB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1865-2103, human PDGFC nucleic acid sequence as set forth in any one of SEQ ID NOS:2271-2395, or human PDGFD nucleic acid sequence as set forth in any one of SEQ ID NOS :2621 -2932.
21. A method for reducing the expression of a human PDGF gene, comprising administering an mdRNA molecule according to any one of claims 1-22 to a cell expressing a human PDGF gene, wherein the mdRNA molecule reduces the expression of the PDGF 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 platelet-derived growth factor (PDGF) mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to any one of PDGFA mRNA as set forth in SEQ ID NO: 1 158 or
1159, human PDGFB mRNA as set forth in SEQ ID NO: 1544 or 1545. human PDGFC mRNA as set forth in SEQ ID NO:2104, or human PDGFD mRNA as set forth in SEQ ID NO:2396 or 2397, and a second strand that is complementary to the
88 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 clarnp, 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 S'-teπninal end comprising a hydroxyl or a phosphate.
30. A dsRNA molecule that down regulates the expression of a human PDGF mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to any one of PDGFA mRNA as set forth in SEQ ID NO:1158 or 1159, human PDGFB mRNA as set forth in SEQ ID NO: 1544 or 1545, human PDGFC mRNA as set forth in SEQ ID NO:2104, or human PDGFD mRNA as set forth in SEQ ID NO:2396 or 2397, 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 1 or II:
89
Figure imgf000008_0001
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, halogen, substituted or unsubstituted Ci -C 10 alkyl, alkoxy, alkoxyalkyl, hydroxy alkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyls substituted or unsubstituted C2-CiO alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted C2-C 10 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-(C1-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-thioribothymidi-ie, or 2'-O-methyl-5- methyluridine.
90
35. The dsRNA molecule of claim 30 wherein the dsRNA molecule comprises at least one LNA, deoxy nucleotide, G clamp, 2'-sugar modification, modified intemucleoside 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 PDGF gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing a PDGF gene, wherein the dsRNA molecule reduces the expression of the PDGF family 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.
91
PCT/US2008/055374 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting pdgf gene expression and uses thereof WO2008109372A2 (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

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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
US93492107P 2007-05-24 2007-05-24
US60/934,921 2007-05-24
US93296807P 2007-05-30 2007-05-30
US93296907P 2007-05-30 2007-05-30
US60/932,968 2007-05-30
US60/932,969 2007-05-30
US93296707P 2007-06-01 2007-06-01
US60/932,967 2007-06-01

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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
CN103597074A (en) * 2011-06-16 2014-02-19 Isis制药公司 Antisense modulation of fibroblast growth factor receptor 4 expression
WO2017134526A1 (en) 2016-02-02 2017-08-10 Olix Pharmaceuticals, Inc. Treatment of angiogenesis-associated diseases using rna complexes that target angpt2 and pdgfb
WO2019002536A1 (en) * 2017-06-30 2019-01-03 Hummingbird Diagnostics Gmbh Novel mirna biomarkers and use thereof

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EP1710307A3 (en) * 2002-02-20 2007-06-06 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA)
AU2003219781A1 (en) * 2002-02-20 2003-09-09 Sirna Therapeutics, Inc RNA INTERFERENCE MEDIATED INHIBITION OF PROLIFERATING CELL NUCLEAR ANTIGEN (PCNA) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA)
US20080199438A1 (en) * 2004-03-16 2008-08-21 Dnavec Research Inc. Methods For Suppressing Tumor Proliferation
JP2008174450A (en) * 2005-04-21 2008-07-31 Univ Nihon Composition for preservation of vascular endothelium
WO2007056153A2 (en) * 2005-11-04 2007-05-18 Nastech Pharmaceutical Company Inc. Peptide-dicer substrate rna conjugates as delivery vehicles for sirna
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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WO2008109474B1 (en) 2008-11-13
WO2008109469A4 (en) 2009-04-09
WO2008109469A3 (en) 2008-12-24
WO2008109474A1 (en) 2008-09-12
WO2008109372A2 (en) 2008-09-12
WO2008109372A3 (en) 2009-02-26

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