WO1999013886B1 - Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications - Google Patents

Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications

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Publication number
WO1999013886B1
WO1999013886B1 PCT/US1998/019419 US9819419W WO9913886B1 WO 1999013886 B1 WO1999013886 B1 WO 1999013886B1 US 9819419 W US9819419 W US 9819419W WO 9913886 B1 WO9913886 B1 WO 9913886B1
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Prior art keywords
group
agent
sense oligonucleotide
receptors
composition
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PCT/US1998/019419
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French (fr)
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WO1999013886A1 (en
Inventor
Jonathan W Nyce
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Univ East Carolina
Jonathan W Nyce
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Priority claimed from US09/093,972 external-priority patent/US6825174B2/en
Application filed by Univ East Carolina, Jonathan W Nyce filed Critical Univ East Carolina
Priority to KR1020007002879A priority Critical patent/KR20010030622A/en
Priority to EP98947089A priority patent/EP1019065A4/en
Priority to JP2000511506A priority patent/JP2003517428A/en
Priority to BR9812650-4A priority patent/BR9812650A/en
Priority to CA002304312A priority patent/CA2304312A1/en
Priority to AU93951/98A priority patent/AU752531B2/en
Priority to IL13514098A priority patent/IL135140A0/en
Publication of WO1999013886A1 publication Critical patent/WO1999013886A1/en
Publication of WO1999013886B1 publication Critical patent/WO1999013886B1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • 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
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Saccharide Compounds (AREA)

Abstract

Antisense oligonucleotides which bind to two or more RNA targets are disclosed.

Claims

AMENDED CLAIMS
[received by the International Bureau on 11 March 1999 (11.03.99); original claims 20 and 24 amended; new claims 59-82 added; remaining claims unchanged (4 pages)]
12. The agent of claim 2, wherein the encoded defensin is selected from the group consisting of the defensin 1, defensin 2, and defensin 3.
13. The agent of claim 2, wherein the encoded selectin is selected from the group consisting of α4βl selectin, α4β7 selectin, LFA-1 selectin, E-selectin, P-selectin. and L-selectin.
14. The agent of claim 2, wherein die mRNA corresponds to an oncogene selected from the group consisting of ras, src, myc, and bcl-2.
15. The agent of claim 1, wherein at least one mononucleotide linking phosphodiester residue of the anti-sense oligonucleotide(s) is substituted by a residue selected from the group consisting of methylphosphonate, phosphotriester. phosphorot oate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone. sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methyimino), methyleneoxy (methylimino), 2'-0-methyl, phosphoramidate residues, and combinations thereof. 16. The agent of claim 15, wherein all phosphodiester residues are substituted.
17. The agent of claim 1, wherein the anti-sense oligonucleotide comprises about 7 to 60 mononucleotides.
18. The agent of claim 1, wherein the oligo consists of up to and including about 15% A.
19. The agent of claim 1, wherein the oligo is adenosine-free.
20. The agent of claim 1 , wherein the anti-sense oligo is selected from the group consisting of oligos comprising SEQ ID NOS. : 1 through 93.
21. The agent of claim 1 , wherein at least one A is substituted by a universal base selected from the group consisting of heteroaromatic bases which bind to a thymidine base but have antagonist activity and less than about 0.3 of the adenosine base agonist activity at the adenosine A A2b and A3 receptors, and heteroaromatic bases which have no activity or have an agonist activity at the adenosine A2a receptor.
22. The agent of claim 21, wherein the heteroaromatic bases are selected from the group consisting of pyrimidines and purines, which may be substituted by O, halo,
NH2, SH, SO, S02, S03, COOH and branched and fused primary and secondary amino, alkyl, alkenyl, alkynyi, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy. acyl, cycloacyl, arylacyl, alkynoxy, cycloalkoxy, aroyl. arylthio. arylsulfoxyl. halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynyicycloalkyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloaikyl, which may be further substituted by O, halo, NH2, primary, secondary and tertiary amine. SH. SO, SO,, S03, cycloalkyl. heterocycloalkyl and heteroaryl.
116
23. The agent of claim 22, wherein the pyrimidines and purines are substituted at positions 1, 2, 3, 4, 7 and 8.
24. The agent of claim 23, wherein the pyrimidines and purines are selected from the group consisting of theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline and xantine having the chemical formula
Figure imgf000004_0001
wherein R1 and R2 are independently H, alkyl, alkenyl or alkynyi and R3 is H, aryl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, O- cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH_-alkylamino-ketoxyalkyloxy-aryl and mono and di_lkylai__noalkyl-N-alkyla__ino-S02 aryl. 25. The agent of claim 24, wherein the universal base is selected from the group consisting of 3-nitropyrrole-2'-deoxynucleoside, 5-nitro-indole, 2-deoxyribosyl-(5- nitroindole), 2-deoxyribo__ranosyl-(5-nitroindole), 2'-deoxyinosine, 2'-deoxynebularine, 6H, 8H-3,4-dihydropyrimido [4,5-c] oxazine-7-one or 2-a_Qino-6-methoxy___inopurine.
26. The agent of claim 1, where a methylated cytocine CQ is substituted for at least one CpG dinucleotide if present in the oligo(s).
27. The agent of claim 1, wherein the anti-sense oligonucleotide is operatively linked to a cell internalized or up-taken agent or to a eukaryotic or prokaryotic vector.
28. The agent of claim 27, wherein the cell internalized or up taken agent is selected from the group consisting of transferrin, asialoglycoprotein, and streptavidin.
29. A composition, comprising the agent of claim 1 and a pharmaceutically or veterinarily acceptable carrier.
30. The composition of claim 29, wherein the carrier is selected from the group consisting of gaseous, liquid and solid carriers. 31. The composition of claim 29, further comprising an agent selected from the group consisting of other therapeutic compounds, surfactants, antioxidants, flavoring and coloring agents, fillers, volatile oils, buffering agents, dispersants, RNA inactivating agents, antioxidants, flavoring agents, propellants and preservatives.
32. The composition of claim 29, wherein the anti-sense oligonucleotide is present in an amount of about 0.01 to about 99.99 w/w of the composition.
33. The composition of claim 32, comprising the nucleic acid, a surfactant and a carrier.
34. The composition of claim 33, wherein the surfactant is selected from the
117
59. The method of claim 52. wherein one of the target proteins comprises the Nf B transcription factor.
60. The method of claim 52, wherein the disease or condition is associated with inflammation, and at least one of the target mRNA encodes a protein selected from the group consisting of interleukins, chemokines, Rantes and receptors thereof.
61. The method of claim 52, wherein the disease or condition is associated with an allergy, and the mRNA encodes a target selected from the group consisting of immunoglobulins and antibody receptors.
62. The me±od of claim 52, wherein the disease or condition is associated with a malignancy or cancer, and the mRNA encodes a target selected from me group consisting of oncogenes, immunoglobulins and antibody receptors.
63. The method of claim 52, wherein the composition is administered by a transdermal or systemic route.
64. The mediod of claim 63, wherein the composition is administered orally, intracavitarily, intra asally, intraanally, intravaginally, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intratumorously, intraglandularly, intraocularly, intracranial, into an organ, intravascularly, intrathecally, by implantation, by inhalation, intradermally, intrapulmonarily, into the ear, by slow release, by sustained release, by a pump and intradermally. 65. The method of claim 52, wherein the subject is selected from the group consisting of vertebrates.
66. The method of claim 65, wherein the subject is selected from the group consisting of mammals.
67. The method of claim 66, wherein the mammals are selected from the group consisting of humans, and small and large, wild and domesticated, marine and farm animals.
68. The method of claim 66, wherein the mammals are selected from the group consisting of human and domesticated and farm animals.
69. The method of claim 52, wherein at least one of the target mRNAs and the subject are of the same species.
70. The memod of claim 52, wherein at least one of the target mRNAs and the subject are human.
71. The method of claim 52, wherein the anti-sense oligonucleotide is administered in an amount of about 0.005 to about 150 mg/kg body weight. 72. The method of claim 71, wherein the anti-sense oligonucleotide is administered in an amount of about 0.01 to about 75 mg/kg body weight.
73. The method of claim 72, wherein the anti-sense oligonucleotide is administered in an amount of about 1 to 50 mg/kg body weight.
118
74. The method of claim 52, being a prophylactic method.
75. The method of claim 52, being a therapeutic method.
76. A method of producing a multiple target anti-sense oligonucleotide, comprising selecting two or more targets selected from ώe group consisting of genes, genomic flanking regions, RNA segments and proteins known to be associated with at least one disease or condition; obtaining RNAs selected from the group consisting of RNAs corresponding to the genes and genomic flanking regions, and RNAs encoding the target proteins; selecting a segment of a first RNA which is at least about 60% homologous to a segment of at least a segment of a second RNA; and synthesizing one or more anti-sense oligonucleotide(s) to the one or more RNA segments.
77. The method of claim 76, further comprising substituting a universal base for at least one non-homologous nucleotide in the anti-sense oligonucleotide.
78. The method of claim 76, further comprising substituting a methylated cytosine for cytosine in at least one CpG dinucleotide present in the anti-sense oligonucleotide.
79. The method of claim 76, wherein the anti-sense oligonucleotide(s) are about 7 to about 60 nucleotides long. 80. The method of claim 76, wherein the target proteins are selected from the group consisting of transcription factors, stimulating and activating factors, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific and non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, selectins, defensines, growth factors, vasoactive peptides, vasoactive peptide receptors, and binding proteins; or the RNA is corresponding to an oncogene.
81. The method of claim 76, wherein the target genes are selected from the group consisting of oncogenes. 82. An anti-sense oligonucleotide produced by the method of claim 76.
119
PCT/US1998/019419 1997-09-17 1998-09-17 Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications WO1999013886A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
KR1020007002879A KR20010030622A (en) 1997-09-17 1998-09-17 Multiple Target Hybridizing Nucleic Acids, Their Preparation, Compositions, Formulation, Kits and Applications
EP98947089A EP1019065A4 (en) 1997-09-17 1998-09-17 Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications
JP2000511506A JP2003517428A (en) 1997-09-17 1998-09-17 Multi-target hybridization nucleic acids, their preparation, compositions, formulations, kits and applications
BR9812650-4A BR9812650A (en) 1997-09-17 1998-09-17 nucleic acids hybridizing multiple labeling, preparation of the same, compositions, formulation, kits and applications
CA002304312A CA2304312A1 (en) 1997-09-17 1998-09-17 Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications
AU93951/98A AU752531B2 (en) 1997-09-17 1998-09-17 Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications
IL13514098A IL135140A0 (en) 1997-09-17 1998-09-17 Multiple target hybridizing nucleic acids, their preparation, compositions, formulation, kits and applications

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US5916097P 1997-09-17 1997-09-17
US60/059,160 1997-09-17
US09/093,972 US6825174B2 (en) 1995-06-07 1998-06-09 Composition, formulations & method for prevention & treatment of diseases and conditions associated with bronchoconstriction, allergy(ies) & inflammation
US09/093,972 1998-06-09

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JP (1) JP2003517428A (en)
KR (1) KR20010030622A (en)
AU (1) AU752531B2 (en)
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CA (1) CA2304312A1 (en)
IL (1) IL135140A0 (en)
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AU9395198A (en) 1999-04-05
JP2003517428A (en) 2003-05-27
KR20010030622A (en) 2001-04-16
IL135140A0 (en) 2001-05-20

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