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ES2564185T3 - Oligonucleótidos no codificantes para la inducción de la omisión exónica y métodos de uso de los mismos - Google Patents

Oligonucleótidos no codificantes para la inducción de la omisión exónica y métodos de uso de los mismos

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ES2564185T3
ES2564185T3 ES10004274.6T ES10004274T ES2564185T3 ES 2564185 T3 ES2564185 T3 ES 2564185T3 ES 10004274 T ES10004274 T ES 10004274T ES 2564185 T3 ES2564185 T3 ES 2564185T3
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omission
coding
oligonucleotide
exon
exonic
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Stephen Donald Wilton
Sue Fletcher
Graham Mcclorey
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University of Western Australia
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Abstract

Un oligonucleótido no codificante aislado que se une al ARN premensajero de la distrofina humana en el que dicho oligonucleótido tiene de 20 a 31 nucleótidos de longitud y es un oligonucleótido que es hibridable de forma específica con una región diana del exón 53 del gen de distrofina, designada como sitio de apareamiento H53A (+23+47), sitio de apareamiento H53A (+39+69), o ambos, en el que dicho oligonucleótido no codificante es un oligonucleótido morfolino no codificante, y, en el que dicho oligonucleótido induce la omisión del exón 53.

Description

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La frase "farmacéuticamente aceptable" se refiere a entidades y composiciones moleculares que son fisiológicamente tolerables y no producen típicamente una reacción alérgica o u otra de tipo adverso semejante, tal como molestia gástrica y similar, cuando se administra a un paciente. El término "vehículo" se refiere a un diluyente, adyuvante, excipiente., o vehículo con el cual se administra el compuesto. Dichos vehículos farmacéuticos pueden ser líquidos estériles, tales como agua y aceites, incluyendo los de origen del petróleo, animal, vegetal o sintético, tal como aceite de cacahuete, aceite de soja, aceite mineral, aceite de sésamo y similares. Las soluciones de agua o salinas y las soluciones acuosas de dextrosa y glicerol se emplean preferentemente como vehículos, concretamente para solución inyectable. En Martin, Remington's Pharmaceutical Sciences, 18ª Ed., Mack Publishing Co., Easton, PA, (1990) se describen vehículos farmacéuticos adecuados.
En una forma más específica de la invención hay composiciones farmacéuticas proporcionadas que comprenden cantidades terapéuticamente eficaces de una molécula no codificante junto con diluyentes, conservantes, solubilizadores, emulsionantes, adyuvantes y/o vehículos farmacéuticamente aceptables. Dichas composiciones incluyen diluyentes con diverso contenido de tampones (p. ej., Tris-HCl, acetato, fosfato), pH y fuerza iónica, y aditivos tales como detergentes y agentes solubilizadores (p. ej., Tween 80, Polisorbato 80), antioxidantes (p. ej., ácido ascórbico, metabisulfito sódico, conservantes (p. ej., tiomerosal, alcohol bencílico) y sustancias espesantes (p. ej., lactosa, manitol). El material puede incorporarse dentro de preparaciones particuladas de compuestos poliméricos tales como ácido poliláctico, ácido poliglicólico, etc. o dentro de liposomas. También puede usarse ácido hialurónico. Dichas composiciones pueden influir sobre el estado físico, la estabilidad, el índice de liberación in vivo, y el índice de eliminación in vivo de las proteínas y derivados presentes. Véase, p. ej., Martin, Remington's Pharmaceutical Sciences, 18ª Ed. (1990, Mack Publishing Co., Easton, PA 18042) páginas1435-1712. Las composiciones líquidas pueden prepararse en forma líquida, o pueden estar en polvo deshidratado, tal como en forma liofilizada.
Se apreciará que las composiciones farmacéuticas proporcionadas de acuerdo con la presente invención puedan administrarse mediante cualquiera de los medios conocidos en la técnica. Preferentemente, las composiciones farmacéuticas para su administración se administran mediante inyección, por vía oral, o mediante vía pulmonar o nasal. Las moléculas no codificantes se suministran más preferentemente mediante las vías de administración intravenosa, intrarterial, intraperitoneal, intramuscular, o subcutánea.
Terapia basada en molécula no codificante
La presente invención también aborda el uso de las moléculas no codificantes de la presente invención, para la fabricación de un medicamento para la modulación de una enfermedad genética.
El suministro de una cantidad terapéuticamente útil de moléculas no codificantes puede lograrse mediante métodos publicados previamente. Por ejemplo, el suministro intracelular de la molécula no codificante puede ser a través de una composición que comprende una mezcla de la molécula no codificante y una cantidad eficaz de un copolímero en bloque. Un ejemplo de este método se describe en la solicitud de patente de EE.UU. US 20040248833.
Otros métodos de suministro de moléculas no codificantes en el núcleo se describen en Mann CJ y col., (2001) ["Antisense-induced exon skipping and the synthesis of dystrophin in the mdx mouse". Proc., Natl. Acad. Science, 98(1) 42-47] y en Gebski y col., (2003). Human Molecular Genetics, 12(15): 1801-1811.
En la patente de EE.UU. US 6.806.084 se describe un método para introducir una molécula de ácido nucleico dentro de una célula por medio de un vector de expresión, bien como ADN desnudo, o bien en complejo con vehículos lipídicos.
Puede ser deseable suministrar la molécula no codificante en un sistema de dispersión coloidal. Los sistemas de dispersión coloidal incluyen complejos de macromoléculas, nanocápsulas, microesferas, perlas, y sistemas a base de lípidos incluyendo emulsiones de aceite en agua, micelas, micelas mixtas, y liposomas o formulaciones de liposomas.
Los liposomas son vesículas de membrana artificial que son útiles como vehículos de suministro in vitro e in vivo. Estas formulaciones pueden tener características de carga neta catiónica, aniónica o neutra y son características útiles con los métodos de suministro in vitro, in vivo y ex vivo. Se ha demostrado que las vesículas unilaminares grandes (VUG), cuyo tamaño oscila desde 0,2-4,0 PHI.m pueden encapsular un porcentaje sustancial de un tampón acuoso que contiene macromoléculas grandes. El ARN y el ADN pueden encapsularse dentro del interior acuoso y suministrarse a las células en una forma biológicamente activa (Fraley, y col., Trends Biochem. Sci., 6:77, 1981).
Para que un liposoma sea un vehículo de transferencia génica eficaz, deberían estar presentes las características siguientes: (1) encapsulación de la molécula no codificante de interés con una alta eficacia, al tiempo que no se compromete su actividad biológica. (2) unión a una célula diana preferente y sustancial en comparación con células no diana; (3) suministro del contenido acuoso de la vesícula al citoplasma de la célula diana con una alta eficacia; y
(4) expresión precisa y eficaz de la información genética (Mannino, y col., Biotechniques, 6:682, 1988).
10
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más cortos o de exón omitido tienden a amplificarse de forma más eficaz y pueden sesgar la estimación del transcrito normal e inducido.
Los tamaños de los productos de la reacción de amplificación se estimaron en un gel de agarosa y se compararon 5 frente a patrones de tamaño apropiados. La confirmación final de la identidad de estos productos se llevó a cabo mediante secuenciación directa del ADN para establecer que se habían mantenido las conexiones de exón correctas
o esperadas.
Una vez se ha inducido la omisión exónica eficaz con una molécula no codificante, las moléculas no codificantes
10 solapantes posteriores pueden sintetizarse y evaluarse después en el ensayo como se ha descrito anteriormente. Nuestra definición de una molécula no codificante eficaz es una que induce omisión exónica fuerte y mantenida a concentraciones de transfección en el orden de 300 nM o menos.
Oligonucleótidos no codificantes dirigidos al exón 53
15 Se prepararon oligonucleótidos no codificantes dirigidos hacia el exón 53 y se ensayó su capacidad de inducir omisión exónica en células musculares humanas usando métodos similares a los descritos anteriormente.
La figura 3 también muestra la molécula no codificante H53A(+39+69) [SEC ID Nº:193] dirigida al sitio aceptor de
20 corte y empalme del exón 53. Este oligonucleótido no codificante fue capaz de inducir omisión del exón 53 a 5, 100, 300 y 600 nM. También se ensayó un "cóctel" de tres oligonucleótidos no codificantes del exón 53:-H53D(+23+47) [SEC ID Nº:195], H53A(+150+175) [SEC ID Nº:196] y H53A(+14-07) [SEC ID Nº:194], como se muestra en la figura 3, y mostraron capacidad para inducir omisión exónica.
25 La tabla 2 a continuación incluye otras moléculas no codificantes ensayadas en un intervalo de concentración de 50, 100, 300 y 600 nM. Estas moléculas no codificantes mostraron una capacidad variable para inducir la omisión del exón 23. La molécula no codificante H53A(+39+69) [SEC ID Nº:193] indujo la omisión más fuerte del exón 53.
Tabla 2 30
Nombre del oligonucleótido no codificante
Secuencia Capacidad de inducir omisión
H53A(+45+69)
CAU UCA ACU GUU GCC UCC GGU UCU G Omisión débil a 50 nM
H53A(+39+62)
CUG UUG CCU CCG GUU CUG AAG GUG Omisión débil a 50 nM
H53A(+39+69)
imagen11 Omisión fuerte a 50 nM
H53D(+14-07)
UAC UAA CCU UGG UUU CUG UGA Omisión muy débil a 50 nM
H53A(+23+47)
CUG AAG GUG UUC UUG UAC UUC AUC C Omisión muy débil a 50 nM
H53A(+150+176)
imagen12 Omisión muy débil a 50 nM
H53D(+20-05)
CUA ACC UUG GUU UCU GUG AUU UUC U Aún sin hacer
H53D(+09-18)
imagen13 Débil a 600 nM
H53A(-12+10)
AUU CUU UCA ACU AGA AUA AAA G Sin omisión
H53A(-07+18)
GAU UCU GAA UUC UUU CAA CUA GAA U Sin omisión
H53A(+07+26)
AUC CCA CUG AUU CUG AAU UC Sin omisión
H53A(+124+145)
UUG GCU CUG GCC UGU CCU AAG A Sin omisión
La invención se define con referencia a las siguientes cláusulas: Cláusula 1: Una molécula no codificante capaz de unirse a un sitio diana seleccionado para inducir omisión exónica 35 en el gen de la distrofina, como se ha expuesto en las SEC ID Nº 1 a 202. Cláusula 2: Una molécula no codificante de acuerdo con la cláusula 1, capaz de inducir omisión exónica en los exones 3, 4, 8, 10 a 16, 19 a 40, 42 a 44, 46, 47 y 50 a 53 del gen de la distrofina. 13

Claims (1)

  1. imagen1
ES10004274.6T 2004-06-28 2005-06-28 Oligonucleótidos no codificantes para la inducción de la omisión exónica y métodos de uso de los mismos Active ES2564185T3 (es)

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AU2004903474A AU2004903474A0 (en) 2004-06-28 Antisense Oligonucleotides for Inducing Exon Skipping and Methods of Use Thereof

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