ES2620472T3 - Compuestos antisentido - Google Patents
Compuestos antisentido Download PDFInfo
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- ES2620472T3 ES2620472T3 ES11186203.3T ES11186203T ES2620472T3 ES 2620472 T3 ES2620472 T3 ES 2620472T3 ES 11186203 T ES11186203 T ES 11186203T ES 2620472 T3 ES2620472 T3 ES 2620472T3
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- lna
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- nucleosides
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- 150000001875 compounds Chemical class 0.000 title description 13
- 230000000692 anti-sense effect Effects 0.000 title description 7
- 239000002777 nucleoside Substances 0.000 abstract description 38
- 239000000074 antisense oligonucleotide Substances 0.000 abstract description 15
- 238000012230 antisense oligonucleotides Methods 0.000 abstract description 15
- 108091034117 Oligonucleotide Proteins 0.000 abstract description 8
- -1 bicyclic nucleoside Chemical class 0.000 abstract description 5
- 125000003835 nucleoside group Chemical group 0.000 description 28
- YIMATHOGWXZHFX-WCTZXXKLSA-N (2r,3r,4r,5r)-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolane-2,4-diol Chemical compound COCCO[C@H]1[C@H](O)O[C@H](CO)[C@H]1O YIMATHOGWXZHFX-WCTZXXKLSA-N 0.000 description 20
- 230000004048 modification Effects 0.000 description 16
- 238000012986 modification Methods 0.000 description 16
- ABEXEQSGABRUHS-UHFFFAOYSA-N 16-methylheptadecyl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC(C)C ABEXEQSGABRUHS-UHFFFAOYSA-N 0.000 description 13
- 241000764238 Isis Species 0.000 description 13
- 238000005417 image-selected in vivo spectroscopy Methods 0.000 description 13
- 238000012739 integrated shape imaging system Methods 0.000 description 13
- 239000002773 nucleotide Substances 0.000 description 12
- 125000003729 nucleotide group Chemical group 0.000 description 12
- 108020004999 messenger RNA Proteins 0.000 description 9
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 8
- 108090000340 Transaminases Proteins 0.000 description 7
- 102000003929 Transaminases Human genes 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 6
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 6
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 5
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 206010019851 Hepatotoxicity Diseases 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 231100000304 hepatotoxicity Toxicity 0.000 description 4
- 230000007686 hepatotoxicity Effects 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 102000018616 Apolipoproteins B Human genes 0.000 description 2
- 108010027006 Apolipoproteins B Proteins 0.000 description 2
- 101100346155 Caenorhabditis elegans oma-2 gene Proteins 0.000 description 2
- 241001346558 Pseudognaphalium sandwicensium Species 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 101710203526 Integrase Proteins 0.000 description 1
- 206010067125 Liver injury Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 150000002243 furanoses Chemical group 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 125000001644 phenoxazinyl group Chemical class C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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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
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
-
- 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
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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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
-
- 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
- C12N2310/11—Antisense
-
- 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
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- 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
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- 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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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/341—Gapmers, i.e. of the type ===---===
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/351—Conjugate
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/53—Methods for regulating/modulating their activity reducing unwanted side-effects
Abstract
Un oligonucleótido antisentido gapmer que tiene un hueco desoxi y al menos un engarce internucleosídico modificado, una región ala 5' situada en el extremo 5' del hueco desoxi, y una región ala 3' situada en el extremo 3' del hueco desoxi, en donde al menos uno de los nucleósidos bicíclicos 4' a 2' y el ala 5' tiene al menos un nucleósido 2' modificado no biciclíco.
Description
5
15
25
35
45
55
65
14-4, 4-14-2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2, 3-13-4, 4-13-3, 1-12-7, 7-12-1, 2-12-6, 6-12-2, 3-12-5, 5-12-3, 412-4, 1-11-8, 8-11-1, 2-11-7, 7-11-2, 3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-18-1, 1-17-2, 2-17-1, 1-16-3, 3-16-1, 2-16-2, 115-4, 4-15-1, 2-15-3, 3-15-2, 1-14-5, 2-14-4, 4-14-2, 3-14-3, 1-13-6, 6-13-1, 2-13-5, 5-13-2, 3-13-4, 4-13-3, 1-12-7, 712-1, 2-12-6, 6-12-2, 3-12-5, 5-12-3, 4-12-4, 1-11-8, 8-11-1, 2-11-7, 7-11-2, 3-11-6, 6-11-3, 4-11-5, 5-11-4, 1-19-1, 118-2, 2-18-1, 1-17-3, 3-17-1, 2-17-2, 1-16-4, 4-16-1, 2-16-3, 3-16-2, 1-15-5, 2-15-4, 4-15-2, 3-15-3, 1-14-6, 6-14-1, 214-5, 5-14-2, 3-14-4, 4-14-3, 1-13-7, 7-13-1, 2-13-6, 6-13-2, 3-13-5, 5-13-3, 4-13-4, 1-12-8, 8-12-1, 2-12-7, 7-12-2, 312-6, 6-12-3, 4-12-5, 5-12-4, 2-11-8, 8-11-2, 3-11-7, 7-11-3, 4-11-6, 6-11-4, 5-11-5, 1-20-1, 1-19-2, 2-19-1, 1-18-3, 318-1, 2-18-2, 1-17-4, 4-17-1, 2-17-3, 3-17-2, 1-16-5, 2-16-4, 4-16-2, 3-16-3, 1-15-6, 6-15-1, 2-15-5, 5-15-2, 3-15-4, 415-3, 1-14-7. 7-14-1, 2-14-6, 6-14-2. 3-14-5, 5-14-3, 4-14-4, 1-13-8, 8-13-1, 2-13-7, 7-13-2, 3-13-6, 6-13-3, 4-13-5, 513-4, 2-12-8, 8-12-2, 3-12-7, 7-12-3, 4-12-6, 6-12-4, 5-12-5, 3-11-8, 8-11-3, 4-11-7, 7-11-4, 5-11-6, 6-11-5, 1-21-1, 120-2, 2-20-1, 1-20-3, 3-19-1, 2-19-2, 1-18-4, 4-18-1, 2-18-3, 3-18-2, 1-17-5, 2-17-4, 4-17-2, 3-17-3, 1-16-6, 6-16-1, 216-5, 5-16-2, 3-16-4, 4-16-3, 1-15-7, 7-15-1, 2-15-6, 6-15-2, 3-15-5, 5-15-3, 4-15-4, 1-14-8, 8-14-1, 2-14-7, 7-14-2, 314-6, 6-14-3, 4-14-5, 5-14-4, 2-13-8, 8-13-2, 3-13-7, 7-13-3, 4-13-6, 6-13-4, 5-13-5, 1-12-10, 10-12-1, 2-12-9, 9-12-2, 3-12-8, 8-12-3, 4-12-7, 7-12-4, 5-12-6, 6-12-5, 4-11-8, 8-11-4, 5-11-7, 7-11-5, 6-11-6, 1-22-1, 1-21-2, 2-21-1, 1-21-3, 3-20-1, 2-20-2, 1-19-4, 4-19-1, 2-19-3, 3-19-2, 1-18-5, 2-18-4, 4-18-2, 3-18-3, 1-17-6, 6-17-1, 2-17-5, 5-17-2, 3-17-4, 4-17-3, 1-16-7, 7-16-1, 2-16-6, 6-16-2, 3-16-5, 5-16-3, 4-16-4, 1-15-8, 8-15-1, 2-15-7, 7-15-2, 3-15-6, 6-15-3, 4-15-5, 5-15-4, 2-14-8, 8-14-2, 3-14-7, 7-14-3, 4-14-6, 6-14-4, 5-14-5, 3-13-8, 8-13-3, 4-13-7, 7-13-4, 5-13-6, 6-13-5, 4-12-8, 8-12-4, 5-12-7, 7-12-5, 6-12-6, 5-11-8, 8-11-5, 6-11-7 ó 7-11-6. En una realización particular, los oligonucleótidos antisentido de hueco ensanchado de la presente invención tienen un motivo de ala-hueco-ala 2-16-2, 3-14-3 ó 4-12
4.
Como se usa en el presente documento, la expresión “nucleótido modificado de alta afinidad” se refiere a un nucleótido que tiene al menos una base nitrogenada, engarce internucleosídico o resto de azúcar modificado, de modo que la modificación aumenta la afinidad de un compuesto antisentido que comprende el nucleótido modificado por un ácido nucleico diana. Las modificaciones de alta afinidad incluyen, pero sin limitación, BNA, LNA y 2’-MOE.
Como se usa en el presente documento el término “mimético” se refiere a grupos que sustituyen a un azúcar, una base nitrogenada y/o engarce internucleosídico. En general, se usa un mimético en lugar del azúcar o combinación azúcar-engarce internucleosídico, y la base nitrogenada se mantiene para hibridación con una diana seleccionada. Los ejemplos representativos de un mimético de azúcar incluyen, pero sin limitación, ciclohexenilo o morfolino. Los ejemplos representativos de un mimético para una combinación de azúcar-engarce internucleosídico, incluyen, pero sin limitación, ácidos péptido nucleicos (PNA) y grupos morfolino ligados por engarces aquirales no cargados. En algunos casos se usa un mimético en lugar de la base nitrogenada. Los miméticos de base nitrogenada representativos se conocen bien en la técnica e incluyen, pero sin limitación, análogos de fenoxazina tricíclica y bases universales (Berger y col., Nuc Acid Res. 2000, 28: 2911-14, incorporado en el presente documento por referencia). Se conocen bien por los expertos en la materia procedimientos de síntesis de miméticos de azúcar, nucleósidos y bases nitrogenadas.
Como se usa en el presente documento, la expresión “nucleósido bicíclico” o “BNA” se refiere a un nucleósido en el que la parte de furanosa del nucleósido incluye un enlace que conecta dos átomos en el anillo de furanosa, formando de este modo un sistema de anillo bicíclico. Los BNA incluyen, pero sin limitación, α-L-LNA, β-D-LNA, ENA, Oxiamino BNA (2’-O-N(CH3)-CH2-4’) y Aminooxi BNA (2’-N(CH3)-O-CH2-4’).
Como se usa en el presente documento, la expresión “nucleósido bicíclico 4’ a 2’” se refiere a un BNA en el que el enlace que conecta dos átomos del anillo de furanosa enlaza el átomo de carbono 4’ y átomo de carbono 2’ del anillo de furanosa, formando de este modo un sistema de anillo bicíclico. Las estructuras representativas de BNA incluyen pero sin limitación:
Aminooxi BNA Oxiamino BNA 9
5
15
25
- ala 5’
- ala 3’
- Posición de nucleósido (5’ a 3’)
- Tipo de nucleósido/ modificaciones engarce dentro del ala Posición de nucleósido (5’ a 3’) Tipo de nucleósido/ modificaciones engarce dentro del ala
- 1 2
- MOE BNA P=S 1 2 LNA LNA P=S
- 1
- LNA Ninguno 1 2 ENA DNA P=S
- 1 2
- ENA MOE P=O 1 MOE Ninguno
- 1
- ENA Ninguno 1 2 MOE LNA P=S
- 1 2
- MOE LNA P=S 1 2 MOE LNA P=S
- 1 2
- MOE LNA P=S 1 2 LNA MOE P=O
- 1 2
- 2’-F Oxiamino BNA P=S 1 Oxiamino BNA Ninguno
- 1 2
- ENA ENA P=S 1 2 3 ENA ENA MOE P=S; P=O
- 1 2 3
- LNA MOE LNA P=S: P=S 1 2 3 LNA MOE LNA P=S; P=S
- 1 2
- MOE LNA P=S 1 2 LNA MOE P=S
Ciertas alas asimétricas
En ciertas realizaciones, los compuestos oligoméricos comprenden alas asimétricas. En tales realizaciones,
cada uno de los nucleósidos del ala 3’ comprende la misma modificación (o no modificación) y cada uno de los
nucleósidos del ala 5’ comprende la misma modificación (o no modificación), pero las modificaciones del ala 5’ y el
35 ala 3’ son diferentes entre sí.
Ciertos huecos
En ciertas realizaciones, los compuestos oligoméricos comprenden un hueco entre el ala 5’ y el ala 3’. En ciertas realizaciones el hueco comprende cinco, seis, siete, ocho, nueve, diez, once, doce, trece o catorce nucleósidos. En ciertas realizaciones, los nucleósidos del hueco son desoxirribonucleótidos no modificados. En ciertas realizaciones, los nucleósidos del hueco son ribonucleótidos no modificados. En ciertas realizaciones, las modificaciones del hueco (si las hubiera) dan como resultado un compuesto antisentido que, cuando se une a su ácido nucleico diana, soporta la escisión por una RNasa, incluyendo, pero sin limitación, RNasa H.
45 En ciertas realizaciones, los engarces internucleosídicos en el hueco son engarces internucleosídicos de origen natural. En ciertas realizaciones, los engarces internucleosídicos en el hueco son engarces de origen no natural. En ciertas realizaciones tales, los engarces internucleosídicos en el hueco son más resistentes a una o más nucleasas que los engarces internucleosídicos de origen natural. En ciertas realizaciones tales, los engarces internucleosídicos en el hueco son engarces de fosforotioato (P=S). En ciertas realizaciones, los engarces internucleosídicos en el hueco son todos iguales entre sí. En ciertas realizaciones, los engarces internucleosídicos dentro de hueco no son todos iguales.
En ciertas realizaciones, el hueco comprende al menos 2 nucleósidos. En ciertas realizaciones, el hueco
55 comprende al menos 3 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 4 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 5 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 6 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 7 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 8 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 9 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 10 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 11 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 12 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 13 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 14 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 15 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 16 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 17 nucleósidos. En ciertas realizaciones, el hueco comprende al menos 18 nucleósidos. En ciertas
65 realizaciones, el hueco comprende al menos 19 nucleósidos. En ciertas realizaciones, el hueco comprende al menos
18
5
15
25
35
45
55
65
Los resultados de un estudio tal, usando gapmer 2-10-2 modificados por LNA que tienen diversos números de modificaciones de ala 2’-MOE se resumen en la Tabla 3.
Tabla 3
- Reducción de ARNm Diana y Transaminasas de Hígado después de la Administración de Oligonucleótidos Antisentido Modificados por 2’-MOE y Modificados por LNA
- Nº de ISIS
- ALT AST ARNm de PTEN (% de UTC) Química del Ala
- Solución salina
- 39 68 100,0 N/D
- 394424
- 38 75 89,7 Alas 2’-MOE
- 392056
- 1249 770 32,4 Alas LNA
- 396570
- 51 84 57,8 Alas LNA con un MOE 2’ en la posición 5’ 1
- 396571
- 42 79 63,8 Alas LNA con un MOE 2’ en la posición 5’ 2
- 396574
- 36 67 71,0 2’-MOE en el ala 5’ LNA en el ala 3’
- 396572
- 497 327 48,8 Alas LNA con un 2’-MOE en la posición 3’ 13
- 396573
- 531 316 46,7 Alas LNA con un 2’-MOE en la posición 3’ 14
- 396575
- 473 341 41,8 LNA en el ala 5’ 2’-MOE en el ala 3’
La administración de oligonucleótidos antisentido gapmer 2-10-2 con alas de nucleótidos 2’-MOE (ISIS 394424) tenían niveles de ALT/AST que son adecuados con los niveles descritos en la técnica asociados con otros oligonucleótidos antisentido gapmer 2’MOE. Por el contrario, el oligonucleótido antisentido gapmer con alas modificadas con LNA (ISIS 392056) redujo el ARNm diana (PTEN), pero dio como resultado niveles gravemente elevados de transaminasas de hígado en suero de ratones tratados, lo que indica hepatotoxicidad. Los oligonucleótidos antisentido gapmer que tienen nucleótidos 2’-MOE añadidos a las regiones ala 3’ y 5’ dieron como resultado una mitigación de las transaminasas en suero elevadas causadas por el gapmer de LNA, ISIS 392056. Los gapmer con modificación 2’-MOE de solamente las alas 5’ (uno o ambos nucleótidos) de oligonucleótidos antisentido modificados con LNA (ISIS 396570, ISIS 396571 y ISIS 396574) dieron como resultado concentraciones de transaminasa en suero cercanas a las del oligonucleótido antisentido gapmer 2’MOE (ISIS 394424) después de administración a ratones, lo que indica que la sustitución de nucleósido o nucleósidos LNA específicos con nucleósido o nucleósidos 2’ modificados proporcionó un compuestos con un perfil de hepatotoxicidad mejorado. Estos compuestos también redujeron el ARNm de PTEN diana en relación con el UTC. La modificación 2’-MOE de los nucleótidos del ala 3’ (ISIS 396572, ISIS 396573, ISIS 396575) dio como resultado la mitigación de la elevación de transaminasas causada por el oligonucleótido antisentido gapmer LNA. Juntos, estos datos indican que la modificación 2’-MOE de los nucleótidos de ala pueden mitigar la hepatotoxicidad de gapmer de LNA 2-10-2 a niveles que son proporcionados para otros gapmer 2’-MOE, mientras que mantienen la reducción del ARNm diana.
Ejemplo 4
Compuestos Antisentido Gapmer 2-10-2 Cortos con Conjugados C16 en Nucleótido 5’ Terminal que se Dirigen a ApoB.
Los estudios descritos en el presente documento se realizaron usando dos oligonucleótidos antisentido gapmer 2-10-2 modificados para determinar si la modificación de nucleótidos podría mitigar la hepatotoxicidad asociada con el resto de ácido nucleico bloqueado (LNA). Las secuencias y motivos de compuestos antisentido se muestran en la Tabla 4. Cada compuestos se dirige a secuencias de ApoB publicadas incluyendo Nº de Acceso de Genbank U92437.1 (SEC ID Nº: 7), (sitio 140). Cada compuesto es un gapmer 2-10-2 (shortmer), que es de 14 nucleótidos de longitud que tiene una región “hueco” central que consiste en diez 2’-desoxinucleótidos que están flanqueados por una región “ala” 5’ y una 3’, cada una de 2 nucleótidos de longitud. Como se muestra en la Tabla 4, los nucleótidos ala de los compuestos ASO individuales portan modificaciones de azúcares distintas. Cada
29
Tabla 8
5
15
- Compuestos Antisentido LNA Cortos con Modificaciones MOE
- Nº de ISIS
- Secuencia SEC ID Nº
- 394420
- meCeTeGCTAGCCTCTGGATTeTe 10
- 394425
- meClTlGCTAGCCTCTGGATTlTl 10
- 399700
- meCeTlGCTAGCCTCTGGATTlTl 10
- 399701
- meClTeGCTAGCCTCTGGATTlTl 10
- 399702
- meCeTeGCTAGCCTCTGGATTlTl 10
- 399703
- meC1T1GCTAGCCTCTGGATTeTe 10
- 400521
- C5lU5lGCTAGCCTCTGGATU5lU5l 10
- 400522
- C6lU6lGCTAGCCTCTGGATU6lU6l 10
- 400523
- C6lU6lGCTAGCCTCTGGATU6lU6l 10
- 400524
- C6lU6lGCTAGCCTCTGGATU6lU6l 10
- 400525
- C6lU6lGCTAGCCTCTGGATU6lU6l 10
25 Se proporcionó a ratones macho Balb/c de 6 semanas de edad (Jackson Laboratory. Bar Harbor, ME) una inyección intraperitoneal sencilla de 10 ó 2 µmol/kg de un oligonucleótido antisentido PTEN (ASO) de la Tabla 9. Los ratones se sacrificaron 72 horas después de la inyección de ASO o control (solución salina) y las concentraciones en suero de transaminasas de hígado (alanina aminotransferasa) [ALT] y aspartato aminotransferasa [AST]) se midieron en unidades internacionales (UI)/l como indicadores de daño del hígado, usando procedimientos bien conocidos por los expertos habituales en la materia. Los niveles de ARNm diana (PTEN) en el hígado se determinaron por procedimientos bien conocidos por los expertos habituales en la materia y la reducción del ARNm diana se enumeró como porcentaje de control no tratado (% de UTC). Los resultados se resumen en la Tabla 9.
Tabla 9
35
45
55
65
- Reducción de ARNm Diana y Transaminasas de Hígado Después de la Administración de Oligonucleótidos Antisentido Modificados por LNA y Modificados por 2’-MOE
- Nº de ISIS
- Dosis (µmol/kg) ALT AST ARNm de PTEN (% de UTC) Química de ala
- Solución salina
- 39 66 100 N/D
- 394420
- 2 30 78 79 Alas 2’-MOE
- 10
- 49 91 26
- 394425
- 2 41 78 11 Alas LNA
- 10
- 2453 2240 2
- 399700
- 2 45 148 36 Alas LNA con un 2’-MOE en la pos. 5’ 1
- 10
- 71 245 6
- 399701
- 2 42 140 48 Alas LNA con un 2’-MOE en la pos. 5’ 2
- 10
- 40 109
- 10
- 399702
- 2 36 78 69 2’-MOE en ala 5’ LNA en ala 3’
- 10
- 41 99 19
- 399703
- 2 33 99 17 LNA en ala 5’ 2’-MOE en ala 3’
- 10
- 807 731 2
- 400521
- 2 37 81 21 5l = alas 5’-(S)-Me-BNA
- 10
- 152 182 4
- 2
- 44 113 18
- 10
- 794 696 4
- 2
- 43 153 17
- 10
- 1374 818 4
- 2
- 31 59 23
- 10
- 269 263 4
- 2
- 43 110 21
- 10
- 765 636 3
- *pos. = posición en secuencia de nucleótidos
32
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