ES2546829T3 - Métodos y composiciones para la inhibición mediada por iARN de la expresión génica en mamíferos - Google Patents
Métodos y composiciones para la inhibición mediada por iARN de la expresión génica en mamíferos Download PDFInfo
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- ES2546829T3 ES2546829T3 ES10178509.5T ES10178509T ES2546829T3 ES 2546829 T3 ES2546829 T3 ES 2546829T3 ES 10178509 T ES10178509 T ES 10178509T ES 2546829 T3 ES2546829 T3 ES 2546829T3
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Abstract
Una composición farmacéutica para su uso en un método de tratamiento que comprende administrar la composición a un mamífero adulto para reducir la expresión de una secuencia diana en el hígado de dicho mamífero adulto, comprendiendo la composición un vehículo farmacéuticamente aceptable y: un agente de iARN seleccionado de un ARNip o un ARNhp, en el que dichos ARNip o ARNhp son específicos para una secuencia diana presente en una célula hepática de dicho mamífero adulto y reducen la expresión de la secuencia diana y en donde el ARNip o el ARNhp tienen una longitud de entre 15 y 30 nucleótidos o tienen una estructura dúplex de 15 a 29 pares de bases de longitud; o un vector que comprende ADN que se transcribe in vivo en dichos ARNhp o ARNip.
Description
E10178509
07-09-2015
10:1735-1737: y Zhang et al., Gene Ther. (1999) 7:1344-1349; son de interés.
Protocolos de administración de ácido nucleico adicionales de interés incluyen, pero no se limitan a: aquellos descritos en las patentes de EE.UU. de interés incluyen 5.985.847 y 5.922.687 (cuyas divulgaciones se incorporan 5 en el presente documento por referencia); documento WO/11092; Acsadi et al., New Biol. (1991) 3:71-81; Hickman et al., Hum. Gen. Ther. (1994) 5:1477-1483; y Wolff et al., Science (1990) 247: 1465-1468; etc.
Dependiendo de la naturaleza del agente de iARN, el (los) agente(s) activo(s) puede(n) administrarse al huésped usando cualquier medio conveniente que pueda producir la modulación deseada de la expresión del gen diana. Así, el agente puede incorporarse en varias formulaciones para administración terapéutica. Más particularmente, los agentes de la presente invención pueden formularse en composiciones farmacéuticas por combinación con vehículos o diluyentes farmacéuticamente aceptables apropiados, y pueden formularse en preparaciones en formas sólidas, semi-sólidas, líquidas o gaseosas, tales como comprimidos, cápsulas, polvos, gránulos, pomadas, disoluciones, supositorios, inyecciones, inhalantes y aerosoles. Como tal, la administración de los agentes puede
15 lograrse de diversas formas, que incluyen administración oral, bucal, rectal, parenteral, intraperitoneal, intradérmica, transdérmica, intratraqueal, etc.
En las formas de dosificación farmacéuticas, los agentes pueden administrarse solos o en asociación apropiada, además de en combinación, con otros compuestos farmacéuticamente activos. Los siguientes métodos y excipientes son simplemente a modo de ejemplo y de ninguna forma son limitantes.
Para preparaciones orales, los agentes pueden usarse solos o en combinación con aditivos apropiados para preparar comprimidos, polvos, gránulos o cápsulas, por ejemplo, con aditivos convencionales, tales como lactosa, manitol, almidón de maíz o almidón de patata; con aglutinantes, tales como celulosa cristalina, derivados de
25 celulosa, goma arábiga, almidón de maíz o gelatinas; con disgregantes, tales como almidón de maíz, almidón de patata o carboximetilcelulosa de sodio; con lubricantes, tales como talco o estearato de magnesio; y si se desea, con diluyentes, agentes de tamponamiento, agentes humidificantes, conservantes y aromatizantes.
Los agentes pueden formularse en preparaciones para inyección disolviéndolos, suspendiéndolos o emulsionándolos en un disolvente acuoso o no acuoso, tal como aceites vegetales u otros similares, glicéridos de ácidos alifáticos sintéticos, ésteres de ácidos alifáticos superiores o propilenglicol; y si se desea, con aditivos convencionales tales como solubilizantes, agentes isotónicos, agentes de suspensión, agentes emulsionantes, estabilizadores y conservantes.
35 Los agentes pueden utilizarse en formulación en aerosol para administrarse mediante inhalación. Los compuestos de la presente invención pueden formularse en propulsores aceptables presurizados tales como diclorodifluorometano, propano, nitrógeno y similares.
Además, los agentes pueden prepararse en supositorios mezclando con varias bases tales como bases emulsionantes o bases solubles en agua. Los compuestos de la presente invención pueden administrarse rectalmente mediante un supositorio. El supositorio puede incluir vehículos tales como manteca de cacao, carboceras y polietilenglicoles, que funden a temperatura corporal, pero están solidificados a temperatura ambiente.
Pueden proporcionarse formas de dosificación unitaria para administración oral o rectal tales como jarabes, elixires y
45 suspensiones en las que cada unidad de dosificación, por ejemplo, cucharadita al ras, cucharada grande, comprimido o supositorio, contenga una cantidad predeterminada de la composición que contiene uno o más inhibidores. Similarmente, las formas de dosificación unitaria para inyección o administración intravenosa pueden comprender el (los) inhibidor(es) en una composición como solución en agua estéril, solución salina normal u otro vehículo farmacéuticamente aceptable.
El término “forma de dosificación unitaria”, como se usa en el presente documento, se refiere a unidades físicamente discretas adecuadas como dosificaciones unitarias para sujetos humanos y animales, conteniendo cada unidad una cantidad predeterminada de compuestos de la presente invención calculada en una cantidad suficiente para producir el efecto deseado en asociación con un diluyente, excipiente o vehículo farmacéuticamente aceptable. Las
55 memorias descriptivas para las novedosas formas de dosificación unitaria de la presente invención dependen del compuesto particular empleado y el efecto que va a lograrse, y la farmacodinámica asociada a cada compuesto en el huésped.
Los excipientes farmacéuticamente aceptables, tales como vehículos, adyuvantes, vehículos o diluyentes, están fácilmente disponibles para el público. Además, sustancias auxiliares farmacéuticamente aceptables, tales como agentes de ajuste del pH y de tamponamiento, agentes de ajuste de la tonicidad, estabilizadores, agentes humectantes y similares, están fácilmente disponibles para el público.
Aquellos expertos en la materia apreciarán fácilmente que los niveles de dosis pueden variar en función del
65 compuesto específico, la naturaleza del vehículo de administración, y similares. Dosificaciones preferidas para un compuesto dado son fácilmente determinables por aquellos expertos en la materia mediante varios medios.
7
E10178509
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indica un compuesto o agente que al menos reduce la actividad de, si no la inactiva completamente, una actividad de RNasa en el organismo multi-celular. En muchas realizaciones, el inhibidor de RNasa es un inhibidor de proteínas de RNasa, siendo el inhibidor placentario humano de RNasa de interés particular. El inhibidor de proteínas de RNasa puede purificarse de una fuente natural o producirse sintéticamente, por ejemplo, mediante técnicas
5 recombinantes. El inhibidor placentario humano de RNasa puede obtenerse de varias fuentes diferentes bajo varios nombres comerciales diferentes, incluyendo fuentes representativas: Promega, Inc., Strategene, Inc., Fisher Scientific, Inc., y similares.
Aunque el inhibidor de RNasa puede administrarse, en ciertas realizaciones, al huésped en una composición
10 separada de la composición de ARN desnudo acuosa, en muchas realizaciones el inhibidor de RNasa está presente en la composición de ARN desnudo acuosa. La cantidad de inhibidor de RNasa que está presente en la composición acuosa es suficiente para proporcionar la captación deseada del ARN desnudo. Si el inhibidor de RNasa es un inhibidor de proteínas, la concentración del inhibidor en la composición acuosa que se introduce en el organismo multi-celular durante la práctica de los métodos objeto puede oscilar de aproximadamente 4 a 4.000 unidades,
15 normalmente de aproximadamente 400 a 4.000 unidades y más normalmente de aproximadamente 400 a 1.500 unidades.
En ciertas realizaciones, el ARN desnudo e inhibidor de RNasa se administran conjuntamente con un ARN competidor. Por ARN competidor se indica un ARN que puede servir de inhibidor competitivo de la actividad de 20 RNasa. En muchas realizaciones, el ARN competidor no tiene casquete y no está poliadenilado. Por no tiene casquete se indica que el ARN competidor carece de la estructura de casquete encontrada en el extremo 5' de ARN mensajero eucariota, es decir, carece de una 7 metil G en 5'. Por no poliadenilado se indica que el ARN competidor carece de una cola de poli A o dominio de poliadenilación en su extremo 3', como se encuentra en ARN mensajero eucariota. La longitud del ARN competidor puede variar, pero es generalmente al menos aproximadamente 70 nt, 25 normalmente al menos aproximadamente 200 nt y más normalmente al menos aproximadamente 1.500 nt, pudiendo ser la longitud tan grande como 10.000 nt o mayor, pero generalmente no supera aproximadamente 3.500 nt y normalmente no supera aproximadamente 1.500 nt. La concentración de ARN competidor en la composición acuosa es suficiente para proporcionar la protección deseada del ARN desnudo (por ejemplo, mediante la competición para la unión por RNasa), y en muchas realizaciones oscila de aproximadamente 10 µg/ml a 10 mg/ml, normalmente de
30 aproximadamente 20 a 200 µg/ml y más normalmente de aproximadamente 40 a 150 µg/ml.
Los métodos descritos producen transferencia altamente eficaz del ARN administrado en el citoplasma de la(s) célula(s) diana. Los métodos descritos son particularmente aptos para transferir ARN al citoplasma del hígado o células hepáticas y células no parenquimatosas en el hígado. Como tal, en muchas realizaciones, los métodos
35 descritos son métodos in vivo de lograr ácido nucleico de alto nivel, por ejemplo, ARN, transferencia en células hepáticas o tejido hepático.
El ácido nucleico que se introduce en la célula diana mediante los métodos descritos tiene vida corta una vez dentro de la célula diana. Dependiendo de la naturaleza particular del ácido nucleico, la semivida del ácido nucleico tras la 40 introducción mediante los métodos objeto generalmente oscila de aproximadamente 30 s a 10 días, normalmente de aproximadamente 1 min a 24 h, y más normalmente de aproximadamente 5 min a 10 h. Como tal, si el ácido nucleico es un ARN que codifica una proteína de interés, la expresión de proteínas tras la introducción mediante el método objeto es transitoria, durante normalmente durante un periodo de tiempo que oscila de aproximadamente 1 min a 3 días, normalmente de aproximadamente 5 min a 24 h. Como tal, en muchas realizaciones de los métodos
45 descritos, los métodos son métodos de proporcionar la expresión transitoria de proteínas de un transgén, en el que la expresión de proteínas es igual a la vida del ARN. Sin embargo, la proteína expresada puede tener una vida más larga, dependiendo de la naturaleza de la proteína particular.
UTILIDAD
50 Los métodos descritos encuentran uso en varias aplicaciones diferentes en las que se desea la transferencia in vivo eficiente de un ácido nucleico desnudo en una célula diana. Aplicaciones en las que los métodos descritos encuentran uso incluyen tanto aplicaciones terapéuticas como de investigación. Aplicaciones terapéuticas de interés incluyen aplicaciones de terapia génica, aplicaciones de vacunación y similares. Aplicaciones de investigación de
55 interés incluyen la producción de modelos animales para afecciones particulares, por ejemplo, infecciones virales de ARN, la observación de expresión génica en fenotipos para aclarar la función génica, etc. Otras aplicaciones en las que el método descrito encuentra uso incluyen el desarrollo de antisentido, ribozima y quimeraplastia (es decir, la reparación de genes mediante agentes terapéuticos de quimeras de ARN/ADN (véase, por ejemplo, Yoon et al., Proc Natl Acad Sci U S A (1996) 93(5):2071-6; Cole-Strauss et al., Science (1996) 273(5280):1386-9; y Zhu et al.,
60 Proc Natl Acad Sci U S A (1999) 96(15):8768-73), además de agentes terapéuticos de ARN interferente (ARN cuya presencia en la célula previene la traducción de ARN similares (véase, por ejemplo, Wianny et al., Nat Cell Biol (2000) 2(2):70-5; y SiQun et al., Nature (1998) 391: 806 -811).
12
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- 2002-07-19 DK DK02761123.5T patent/DK1409506T3/da active
- 2002-07-19 EP EP02761123A patent/EP1409506B1/en not_active Expired - Lifetime
- 2002-07-19 ES ES02761123T patent/ES2386775T3/es not_active Expired - Lifetime
- 2002-07-19 DK DK10178509.5T patent/DK2280070T3/en active
- 2002-07-19 CA CA2454183A patent/CA2454183C/en not_active Expired - Lifetime
- 2002-07-19 AT AT02761123T patent/ATE556720T1/de active
- 2002-07-19 JP JP2003515539A patent/JP2005508306A/ja not_active Withdrawn
- 2002-07-19 PT PT101785095T patent/PT2280070E/pt unknown
- 2002-07-19 ES ES10178509.5T patent/ES2546829T3/es not_active Expired - Lifetime
-
2004
- 2004-10-16 HK HK04108019.6A patent/HK1065562A1/xx not_active IP Right Cessation
-
2010
- 2010-11-08 JP JP2010249697A patent/JP6055164B2/ja not_active Expired - Lifetime
-
2013
- 2013-07-12 US US13/941,262 patent/US10517887B2/en not_active Expired - Fee Related
-
2014
- 2014-09-16 JP JP2014187281A patent/JP2015044809A/ja active Pending
-
2016
- 2016-08-17 JP JP2016159918A patent/JP6247355B2/ja not_active Expired - Lifetime
-
2019
- 2019-12-20 US US16/723,744 patent/US20200246370A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP2280070A1 (en) | 2011-02-02 |
US20130312126A1 (en) | 2013-11-21 |
WO2003010180A1 (en) | 2003-02-06 |
PT2280070E (pt) | 2015-10-29 |
US10517887B2 (en) | 2019-12-31 |
HK1065562A1 (en) | 2005-02-25 |
JP6055164B2 (ja) | 2016-12-27 |
CA2936534C (en) | 2021-01-26 |
JP2011093906A (ja) | 2011-05-12 |
JP2005508306A (ja) | 2005-03-31 |
JP2017008084A (ja) | 2017-01-12 |
CA2454183C (en) | 2016-09-06 |
DK1409506T3 (da) | 2012-08-06 |
US20030153519A1 (en) | 2003-08-14 |
EP1409506B1 (en) | 2012-05-09 |
ATE556720T1 (de) | 2012-05-15 |
EP2280070B1 (en) | 2015-05-20 |
JP2015044809A (ja) | 2015-03-12 |
DK2280070T3 (en) | 2015-08-24 |
US20200246370A1 (en) | 2020-08-06 |
ES2386775T3 (es) | 2012-08-30 |
CA2936534A1 (en) | 2003-02-06 |
EP1409506A1 (en) | 2004-04-21 |
EP1409506A4 (en) | 2004-11-17 |
CA2454183A1 (en) | 2003-02-06 |
JP6247355B2 (ja) | 2017-12-13 |
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