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WO2008109375A4 - Nucleic acid compounds for inhibiting pik3c gene expression and uses thereof - Google Patents

Nucleic acid compounds for inhibiting pik3c gene expression and uses thereof Download PDF

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Publication number
WO2008109375A4
WO2008109375A4 PCT/US2008/055377 US2008055377W WO2008109375A4 WO 2008109375 A4 WO2008109375 A4 WO 2008109375A4 US 2008055377 W US2008055377 W US 2008055377W WO 2008109375 A4 WO2008109375 A4 WO 2008109375A4
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human
strand
mrna
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seq
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WO2008109375A9 (en
WO2008109375A3 (en
WO2008109375A2 (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 WO2008109375A9 publication Critical patent/WO2008109375A9/en
Publication of WO2008109375A3 publication Critical patent/WO2008109375A3/en
Publication of WO2008109375A4 publication Critical patent/WO2008109375A4/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]
    • 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
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed

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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 PIK3C 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 PIK3C 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 PIK3C gene in a cell or in a subject to treat a PIK3C-related disease.

Claims

AMENDED CLAIMS received by the International Bureau on 11 March 2009 (11.03.09)WHAT IS CLAIMED IS:
1. A meroduplex ribonucleic acid (mdRNA) molecule that down regulates the expression of any one of human phosphoinositide-3 -kinase, catalytic (PIK3C) mRNA, human PK3CB mRNA, human PIK3CD mRNA, human PIK3CG niRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human PIK3C mRNA as set forth in SEQ ID NO:1158, human PIK3CB mRNA as set forth in SEQ ID NO:1519, human PIK3CD mRNA as set forth in SEQ ID NO: 1833 or 1834, or human PIK3CG mRNA as set forth in SEQ ID NO: 3002, 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 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 any one of human PIK3C mRNA, human PIK3CB mRNA, human PDG CD mRNA, human PIK3CG mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human PIK3C mRNA as set forth
AMENDED SHEET (ARTICLE 19) i in SEQ ID NO: 1158, human PIK3CB mRNA as set forth in SEQ ID NO:1519, human PIK3CD mRNA as set forth in SEQ ID NO: 1833 or 1834, or human PIK3CG mRNA as set forth in SEQ ID NO: 3002, 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 imgf000003_0001
wherein:
R1 and R2 are each independently a -H, -OH, -OCH3, -OCH2OCH2CH3, -OCH2CH2OCH3, 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, -0-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 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.
AMENDED SHEET (ARTICLE 19)
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 8 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 any one of human PIK3C mRNA. human PIK3CB mRNA, human P1K3CD mRNA, human PIK3CG mRNA, the mdRNA molecule comprising a first strand of 15 to 40 nucleotides in length that is complementary to the human PIK.3C mRNA as set forth in SEQ ID NO:1 158, human PIK3CB mRNA as set forth in SEQ ID NO: 1519, human PIK3CD mRNA as set forth in SEQ ID NO: 1833 or 1834, or human PDC3CG mRNA as set forth in SEQ ID NO:3002, 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.
AMENDED SHEET (ARTICLE 19)
16. The mdRN A 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.
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 PIK3CA nucleic acid sequence as set forth in any one of SEQ IDNOS:! 159-1518, or human PIK3CB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1520- 1832, or human PIK3CD nucleic acid sequence as set forth in any one of SEQ ID NOS:1835-300l, or human PIK3CG nucleic acid sequence as set forth in any one of SEQ ID NOS:3003- 3522.
20. The mdRNA molecule of claim 15 wherein the first strand is 25 to 29 nucleotides in length and is complementary to a human PIK3CA nucleic acid sequence as set forth in any one of SEQ ID NOS : 1159- 1518, or human PIK3 CB nucleic acid sequence as set forth in any one of SEQ ID NOS: 1520-1832, or human PIK3CD nucleic acid sequence as set forth in any one of SEQ ID NOS:1835-3001, or human PDC3CG nucleic acid sequence as set forth in any one of SEQ ID NOS:3003- 3522.
21. A method for reducing the expression of a human PIK3C, PIK3CB, PIK3CD, or PIK3CG gene, comprising administering an nidRNA molecule according to any one of claims 1-20 to a cell expressing a human PIK3C, PIK3CB, PIK3CD, or PIK3CG gene, wherein the mdRNA molecule reduces the expression of the human PIK3C, PIK3CB, PIK3CD, or PIK3CG gene in the cell.
22. The method according to claim 21 wherein the cell is a human cell.
AMENDED SHEET (ARTICLE 19)
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 any one of human phosphoinositide-3 -kinase, catalytic (PIK3C) mRNA, human PIK3CB mRNA, human PIK3CD mRNA, human PDC3CG mRNA, the dsRNA molecule comprising a first strand of 26 to 40 nucleotides in length that is complementary to the human PIK3C mRNA as set forth in SEQ ID NO: 1158, human PIK3CB mRNA as set forth in SEQ ID NO: 1519, human PIK3CD mRNA as set forth in SEQ ID NO:1833 or 1834, or human PIK3CG mRNA as set forth in SEQ ID NO: 3002, 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-thioribothyniidine, 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 any one of human PIK3C mRNA, human PIK3CB mRNA, human PIK3CD mRNA, human PIK3CG mRNA, the dsRNA molecule comprising a first strand of 26 to 40
AMENDED SHEET (ARTICLE 19) nucleotides in length that is complementary to the human PIK3C mRNA as set forth in SEQ ID NO:1 158, human PDC3CB mKNA as set forth in SEQ ID NO:1519, human PIK3CD mRNA as set forth in SEQ ID NO: 1833 or 1834, or human PIK3CG mRNA as set forth in SEQ ID NO:3002, 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, -OCHiCHaOCH3, halogen, substituted or unsubstituted C]-C1O 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, -0-CH=CHCH3, substituted or unsubstituted C2-C10 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.
AMENDED SHEET (ARTICLE 19)
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-alIyl, 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-mcethyl-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 PIK3C, PIK3CB, PIK3CD, or PIK3CG gene, comprising administering a dsRNA molecule according to any one of claims 24-36 to a cell expressing a human PIK3C, PIK3CB, PHC3CD, or PIK3CG gene, wherein the dsRNA molecule reduces the expression of the human PQC3C, PIK3CB, PIK3CD, or PIK3CG gene in the cell.
38. The method according to claim 37 wherein the cell Ls 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.
AMENDED SHEET (ARTICLE 19)
PCT/US2008/055377 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting pik3c gene expression and uses thereof Ceased WO2008109375A2 (en)

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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

Applications Claiming Priority (12)

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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
US94945007P 2007-07-12 2007-07-12
US60/949,450 2007-07-12
US95117007P 2007-07-20 2007-07-20
US95116707P 2007-07-20 2007-07-20
US95116807P 2007-07-20 2007-07-20
US60/951,168 2007-07-20
US60/951,170 2007-07-20
US60/951,167 2007-07-20

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PCT/US2008/055345 Continuation-In-Part WO2008109355A1 (en) 2007-03-02 2008-02-28 Nucleic acid compounds for inhibiting srd5a2 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
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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WO2009152346A2 (en) * 2008-06-11 2009-12-17 Intradigm Corporation Compositions comprising phosphoinositide 3-kinase sirna and methods of use thereof
WO2011090741A2 (en) * 2009-12-29 2011-07-28 Opko Curna, Llc TREATMENT OF TUMOR PROTEIN 63 (p63) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPT TO p63
US9453261B2 (en) * 2011-09-20 2016-09-27 The George Washington University Alternative splicing variants of genes associated with prostate cancer risk and survival
US10226424B2 (en) * 2012-08-12 2019-03-12 Mylisa Parette Therapeutic calcium phosphate nanoparticle incorporating siRNA useful in treating disease
EP4382118B1 (en) * 2022-12-07 2025-08-20 Eberhard Karls Universität Tübingen, Medizinische Fakultät Modified immune cell

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WO2003070918A2 (en) * 2002-02-20 2003-08-28 Ribozyme Pharmaceuticals, Incorporated Rna interference by modified short interfering nucleic acid
PL1730303T3 (en) * 2004-03-02 2014-04-30 Univ Johns Hopkins Mutations of the pik3ca gene in human cancers
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

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