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WO2008109370A4 - Nucleic acid compounds for inhibiting srd5a1 gene expression and uses thereof - Google Patents

Nucleic acid compounds for inhibiting srd5a1 gene expression and uses thereof Download PDF

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Publication number
WO2008109370A4
WO2008109370A4 PCT/US2008/055372 US2008055372W WO2008109370A4 WO 2008109370 A4 WO2008109370 A4 WO 2008109370A4 US 2008055372 W US2008055372 W US 2008055372W WO 2008109370 A4 WO2008109370 A4 WO 2008109370A4
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WIPO (PCT)
Prior art keywords
strand
molecule
mdrna
nucleotides
human
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2008/055372
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French (fr)
Other versions
WO2008109370A3 (en
WO2008109370A2 (en
Inventor
Steven C Quay
James Mcswiggen
Narendra K Vaish
Mohammad Ahmadian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Marina Biotech Inc
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MDRNA Inc
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Application filed by MDRNA Inc filed Critical MDRNA Inc
Publication of WO2008109370A2 publication Critical patent/WO2008109370A2/en
Publication of WO2008109370A3 publication Critical patent/WO2008109370A3/en
Publication of WO2008109370A4 publication Critical patent/WO2008109370A4/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
Ceased legal-status Critical Current

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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
    • C12N15/1137—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
    • 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]

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  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Health & Medical 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)
  • Virology (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 SRD5A1 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 SRD5A1 mRNA. In addition, the meroduplex may have at least one uridine substituted with 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 an SRD5A1 gene in a cell or in a subject to treat an SRD5 Al -related disease.

Claims

AMENDED CLAIMS received by the International Bureau on 20 November 2008
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of a human steroid-5-alpha-reductase, alpha polypeptide 1 (SRD 5Al) mRNA, comprising a first strand of 15 to 40 nucleotides in length that is complementary to a portion of the human SRD5A1 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 I 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 moJecule that down regulates the expression of a human SRD5A1 mRNA., the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human SRD5A1 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
82 pyrimidine of the mdRNA molecule is a pyrimidine nucleoside according to Foπnula I or II:
Figure imgf000004_0001
wherein:
R1 and R2 are each independently a -H, -OH5 -OCH3, -OCH2OCH2CH3, -OCH2CH2OCHa5 halogen, substituted or unsubstituted C1-CiO alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, carboxyalkyl, alkylsulfonylamino, aminoalkyl, dialkylamino, alkylaminoalkyl. dialkylaminoalkyl, haloalkyl, trifluoromethyl, cycloalkyl, (cycloalkyl)alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -O-CH=CHCH3> substituted or unsubstituted C2-C10 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 Rs 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.
83
11. The mdRNA molecule of claim 7 wherein at least one R2 is selected fixan the group consisting of 2'-O-(Ci-C3) 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 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 SRD5A1 mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human SRD5 Al 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 S-methyluridine, 2-thioribo thymidine, or 2l-O-methyl-5- methyluridine.
84
19. The mdRNA molecule of claim 15 wherein the first strand is 19 to 23 nucleotides in length, and is complementary to a human SRD5A1 nucleic acid sequence as set forth in any one of SEQ ID NOS:1159-1284.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human SRD5A1 nucleic acid sequence as set forth in any one of SEQ ID NOS:244 and 1285-1377.
21. A method for reducing the expression of a human SRD5 A 1 gene, comprising administering an mdRNA molecule according to any one of claims 1-20 to a cell expressing a human SRD5A1 gene, wherein the mdRNA molecule reduces the expression of the human SRD5A1 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 hyperprαliferative or inflammatory disease.
24. A double- stranded ribonucleic acid (dsRNA) molecule that down regulates the expression of a human steroid- 5 -alpha-reductase, alpha polypeptide 1 (SRD5A1) mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human SRD5A1 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-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
85 clamp, 2'-sugar modification, modified intemucleoside 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 dsRN A molecule that down regulates the expression a human SRD5A1 mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to a portion of the human SRD5A1 niRNA 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 -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-CiO alkenyl, substituted or unsubstituted -O-allyl, -0-CH2CH=CH2, -0-CH=CHCH3, substituted or unsubstituted 02-C10 alkynyl, carbamoyl, carbamyl, carboxy, carbonylamino, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, -NH2, -NO2, -C≡N, or heterocyclo group,
AMENDED SHE6ET (ARTICLE 19) R3 and R4 are each independently a hydroxyl, a protected hydroxyl. a phosphate, or an inteπrucleoside linking group, and Rs 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-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 SRD5A1 gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing a human SRD5A1 gene, wherein the dsRNA molecule reduces the expression of the human SRD5A1 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,
87
PCT/US2008/055372 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting srd5a1 gene expression and uses thereof Ceased WO2008109370A2 (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
US94944407P 2007-07-12 2007-07-12
US60/949,444 2007-07-12

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Related Child Applications (3)

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PCT/US2008/055378 Continuation-In-Part WO2008109376A1 (en) 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting bcr-abl 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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AU2007310982A1 (en) 2006-10-18 2008-04-24 Marina Biotech, Inc. Nicked or gapped nucleic acid molecules and uses thereof

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AU2004285134B2 (en) * 2003-10-21 2012-01-19 Dyad Pharmaceutical Corporation Methods and compositions for treating 5alpha-reductase type 1 and type 2 dependent conditions
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EP2002004B1 (en) * 2006-03-23 2015-10-14 Roche Innovation Center Copenhagen A/S Small internally segmented interfering rna
AU2007310982A1 (en) * 2006-10-18 2008-04-24 Marina Biotech, Inc. Nicked or gapped nucleic acid molecules and uses thereof

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