ES2620472T3 - Compuestos antisentido - Google Patents

Compuestos antisentido Download PDF

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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
moe
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nucleosides
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Eric E. Swayze
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Ionis Pharmaceuticals Inc
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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

imagen1
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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:
imagen8
Aminooxi BNA Oxiamino BNA 9
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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
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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
imagen27
imagen28
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
imagen29

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