ES2581285T3 - Inducción de la omisión de exón en células eucariotas - Google Patents

Inducción de la omisión de exón en células eucariotas Download PDF

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ES2581285T3
ES2581285T3 ES13170245.8T ES13170245T ES2581285T3 ES 2581285 T3 ES2581285 T3 ES 2581285T3 ES 13170245 T ES13170245 T ES 13170245T ES 2581285 T3 ES2581285 T3 ES 2581285T3
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exon
cell
mrna
skipping
protein
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Garrit-Jan Boudewijn Van Ommen
Judith Christina Theodora Van Deutekom
Johannes Theodorus Den Dunnen
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Leids Universitair Medisch Centrum LUMC
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Abstract

Un oligonucleótido antisentido dirigido contra el interior del exón 44 del pre-ARNm de distrofina humana, que facilita la ocultación de dicho exón del aparato de corte y empalme, y la exclusión de dicho exón del ARNm final, en donde dicho antisentido no es un ADN o un ADN fosforotioato que consiste en la secuencia nucleótida GCACTTTGCAATGCTGCTGTCTTCTTGCTTAT descrita como SEQ ID NO:3 en el documento de patente EP 1 160 318 o un ADN o un ADN fosforotioatoque consiste en una secuencia nucleótida complementaria a la secuencia nucleótida AGCAAGAAGACAGCAGCAUUGCAAAG descrita como SEQ ID NO:1 en el documento de patente EP 1 160 318.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
datos de secuencia de los fragmentos de RT-PCR truncados. Aquí se muestra la secuencia obtenida del producto de omisión del exón 29 en células tratadas con h29AON#1.
Figura 9:
(A) Análisis de RT-PCR de ARN aislado del músculo gastrocnemio de ratón dos días después de la inyección de 5,
5 10, o 20 µg de mAON#4, #6, o #11. Se detectaron productos truncados, con un tamaño que se corresponde con el exón 45 cortado y empalmado para producir el exón 47, en todos los músculos tratados. Las muestras de -RT, -ARN, AD-1, y AD-2 se analizaron como controles negativos para las reacciones de RT-PCR. (B) El análisis de la secuencia de los productos truncados generados por mAON#4 y #6 (y #11, no se muestra) confirmó la omisión precisa del exón 46.
10 Ejemplos
Ejemplo de referencia 1
Puesto que el exón 45 es uno de los exones que con más frecuencia están delecionados en DMD, en un principio el objetivo fue inducir la omisión específica del exón 46 (figura 1). Esto produciría la distrofina más corta, pero en gran medida funcional, que se encuentra en los pacientes BMD que portan una deleción de los exones 45 y 46. El
15 sistema en principio se constituyó para la modulación del corte y empalme de pre-ARNm de distrofina del gen de distrofina de ratón. Después el objetivo fue el gen de distrofina humano, con la intención de restablecer el marco de lectura traduccional y la síntesis de distrofina en células musculares procedentes de pacientes DMD afectados por una deleción del exón 45.
Diseño de mAON y hAON
20 Se diseñó un serie de AON específicos de ratón y humano (mAON y hAON) dirigidos a una parte interna del exón 46 que contiene un tramo de secuencias ricas en purina, y se establece la hipótesis de que desempeña un papel regulador putativo en el proceso de corte y empalme del exón 46 (figura 2). Para la selección inicial de los AON en los ensayos de desplazamiento de la movilidad en gel (véase a continuación), se utilizaron oligonucleótidos de ADN no modificados (sintetizados por EuroGentec, Bélgica). Para los experimentos de transfección reales en células
25 musculares, se emplearon oligorribonucleótidos de 2'-O-metil-fosforotioato (también sintetizados por EuroGentec, Bélgica). Se sabe que estos oligonucleótidos de ARN modificados son resistentes a endonucleasas y ARNasaH, y que se unen al ARN con alta afinidad. Las secuencias de estos AON que fueron finalmente eficaces y que se aplicaron a células musculares in vitro se muestran a continuación. Los correspondientes AON específicos de ratón y humano son altamente homólogos, pero no completamente idénticos.
30 El siguiente listado se refiere a la forma desoxi utilizada para los ensayos, y en los ribonucleótidos de 2-O-metilo que finalmente se emplearon, todas las T deben leerse como U. mAON#2: 5' GCAATGTTATCTGCTT mAON#3: 5' GTTATCTGCTTCTTCC mAON#4: 5' CTGCTTCTTCCAGCC 35 mAON#5: 5' TCTGCTTCTTCCAGC mAON#6: 5' GTTATCTGCTTCTTCCAGCC mAON#7: 5' CTTTTAGCTGCTGCTC mAON#8: 5' GTTGTTCTTTTAGCTGCTGC mAON#9: 5' TTAGCTGCTGCTCAT 40 mAON#10: 5' TTTAGCTGCTGCTCATCTCC mAON#11: 5' CTGCTGCTCATCTCC hAON#4: 5' CTGCTTCCTCCAACC hAON#6: 5' GTTATCTGCTTCCTCCAACC hAON#8: 5' GCTTTTCTTTTAGTTGCTGC 45 hAON#9: 5' TTAGTTGCTGCTCTT hAON#11: 5' TTGCTGCTCTTTTCC
7
imagen6
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Tabla 1
Exón que se va a omitir
Terapéutica para las DMD (exones) deleciones Frecuencia en http://www. dmd.nl (%)
2
3-7 imagen9
2
8
3-7 imagen10 4
imagen11
4-7 imagen12
imagen13
5-7 imagen14
imagen15
6-7 imagen16
43
44 imagen17 5
imagen18
44-47 imagen19
44
35-43 imagen20 8
imagen21
45 imagen22
imagen23
45-54 imagen24
45
18-44 imagen25 13
imagen26
46-47 imagen27
imagen28
44 imagen29 imagen30
imagen31
46-48 imagen32
imagen33
46-49 imagen34
imagen35
46-51 imagen36
imagen37
46-53 imagen38
46
45 imagen39 7
50
51 imagen40 5
imagen41
51-55 imagen42
51
50 imagen43 15
imagen44
45-50 imagen45
imagen46
48-50 imagen47
imagen48
49-50 imagen49
imagen50
52 imagen51
11
Exón que se va a omitir
Terapéutica para las deleciones DMD (exones) Frecuencia en http://www. dmd.nl (%)
imagen52
52-63
52
51 3
imagen53
53
imagen54
53-55
53
45-52 9
imagen55
48-52
imagen56
49-52
imagen57
50-52
imagen58
52
Aspectos y realizaciones de la descripción
En un primer aspecto, se proporciona un método para dirigir el corte y empalme de un pre-ARNm en un sistema capaz de realizar una operación de corte y empalme, que comprende poner en contacto dicho pre-ARNm en dicho 5 sistema con un agente capaz de inhibir específicamente una señal de inclusión de exón de al menos un exón en dicho pre-ARNm, y dicho método comprende también permitir el corte y empalme de dicho pre-ARNm.
Un método preferido comprende también permitir la traducción del ARNm producido por el corte y empalme de dicho pre-ARNm.
Un método preferido es en el que dicho ARNm codifica una proteína funcional.
10 Un método preferido es en el que dicha proteína comprende dos o más dominios, en los que al menos uno de dichos dominios está codificado por dicho ARNm como resultado de la omisión de al menos parte de un exón en dicho pre-ARNm.
Un método preferido es en el que dicho contacto produce la activación de un sitio de corte y empalme críptico en un exón contactado.
15 En un segundo aspecto, se proporciona un método para disminuir, al menos en parte, la producción de una proteína aberrante en una célula,
y dicha célula comprende un pre-ARNm que comprende exones que codifican dicha proteína, comprendiendo dicho método
proporcionar a dicha célula un agente capaz de inhibir específicamente una señal de inclusión de exón
20 de al menos uno de dichos exones,
y el método comprende también permitir la traducción del ARNm producido por el corte y empalme de dicho pre-ARNm.
Los métodos del primer y segundo aspecto son preferiblemente de modo que dicha señal de inclusión de exón comprende una secuencia de reconocimiento de exón.
25 Los métodos del primer y segundo aspecto son preferiblemente de modo que dicha señal de inclusión de exón está presente en un exón que comprende una pareja de donante/aceptor de corte y empalme fuerte.
Los métodos del primer y segundo aspecto son preferiblemente de modo que dicha traducción produzca una proteína de distrofina mutante o normal, más preferiblemente en el que dicha proteína de distrofina mutante es
12
imagen59

Claims (1)

  1. imagen1
ES13170245.8T 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucariotas Expired - Lifetime ES2581285T3 (es)

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EP00203283A EP1191097A1 (en) 2000-09-21 2000-09-21 Induction of exon skipping in eukaryotic cells
EP00203283 2000-09-21

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ES15166264.0T Expired - Lifetime ES2690049T3 (es) 2000-09-21 2001-09-21 Inducción de omisión de exones en células eucarióticas
ES12198465.2T Expired - Lifetime ES2561292T3 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucariotas
ES12198485.0T Expired - Lifetime ES2561293T3 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucariotas
ES13170251.6T Expired - Lifetime ES2628349T3 (es) 2000-09-21 2001-09-21 Inducción de omisión de exones en células eucarióticas
ES05076770T Expired - Lifetime ES2315788T5 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucarióticas
ES13170245.8T Expired - Lifetime ES2581285T3 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucariotas
ES12198517.0T Expired - Lifetime ES2567417T3 (es) 2000-09-21 2001-09-21 Inducción de las omisiones de exón en las células eucariotas
ES13170239.1T Expired - Lifetime ES2610568T3 (es) 2000-09-21 2001-09-21 Inducción de omisión de exones en células eucarióticas
ES12198497.5T Expired - Lifetime ES2561294T3 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exón en células eucariotas
ES14176300.3T Expired - Lifetime ES2629747T3 (es) 2000-09-21 2001-09-21 Inducción de la omisión de exones en células eucarióticas
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