ES2666559T3 - Entrega del mrna para la aumentación de proteínas y enzimas en enfermedades genéticas humanas - Google Patents
Entrega del mrna para la aumentación de proteínas y enzimas en enfermedades genéticas humanas Download PDFInfo
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Abstract
Una composición farmacéutica para su uso en un método para tratar una enfermedad en un sujeto que resulta de una deficiencia de proteína, la composición farmacéutica que comprende: un vehículo de transferencia y al menos una molécula de ARNm que codifica dicha proteína, el vehículo de transferencia que comprende uno o más lípido(s) catiónico(s), uno o más lípido(s) no catiónico(s) y uno o más lípido(s) modificado(s) con PEG, el vehículo de transferencia es un liposoma y el tamaño del vehículo de transferencia es inferior a 100 nm, en donde la composición farmacéutica se distribuye preferentemente en las células hepáticas después de la administración al sujeto y la proteína codificada se expresa en las células hepáticas del sujeto.
Description
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[0047] La presente invención también contempla el uso de lípidos no catiónicos. Como se usa en el presente documento, la frase "lípido no catiónico" se refiere a cualquier lípido neutro, zwitteriónico o aniónico. Como se usa en este documento, la frase "lípido aniónico" se refiere a cualquiera de varias especies de lípidos que llevan una carga neta negativa a un pH seleccionado, tal como el pH fisiológico. Los lípidos no catiónicos incluyen, pero no se limitan a, diestearoilfosfatidilcolina (DSPC), dioleoilfosfatidilcolina (DOPC), dipalmitoilfosfatidilcolina (DPPC), dioleoilfosfatidilglicerol (DOPG), dipalmitoilfosfatidilglicerol (DPPG), dioleoilfosfatidiletanolamina (DOPE), palmitoiloleoilfosfatidilcolina (POPC), palmitoiloleoílo-fosfatidiletanolamina (POPE), dioleoílo-fosfatidiletanolamina 4(N-maleimidometilo)-ciclohexano-1-carboxilato(DOPE-mal), dipalmitoílo fosfatidiletanolamina (DPPE), dimiristoilfosfoetanolamina (DMPE), diestearoílo-fosfatidilo-etanolamina (DSPE), 16-O-monometilo PE, 16-O-dimetilo PE, 18-1-trans PE, 1-estearoílo-2-oleoílo-fosfatidietanolamina (SOPE), colesterol, o una mezcla de los mismos. Tales lípidos no catiónicos se usan en combinación con otros excipientes, es decir, lípidos catiónicos y lípidos no catiónicos. Cuando se usa en combinación con un lípido catiónico, el lípido no catiónico puede comprender una relación molar de 5% a aproximadamente 90%, o preferiblemente de aproximadamente 10% a aproximadamente 70% del lípido total presente en el vehículo de transferencia.
[0048] El vehículo de transferencia se prepara mediante la combinación de múltiples componentes de lípidos y/o polímeros. Por ejemplo, se puede preparar un vehículo de transferencia usando ceramida DSPC/CHOL/DODAP/C8PEG-5000 en una relación molar de aproximadamente 1 a 50 : 5 a 65 : 5 a 90 : 1 a 25, respectivamente. Un vehículo de transferencia puede estar compuesto de combinaciones de lípidos adicionales en diversas relaciones, que incluyen, por ejemplo, DSPC/CHOL/DODAP/mPEG-5000 (por ejemplo, combinadas en una relación molar de aproximadamente 33: 40: 25: 2), DSPC/CHOL/DODAP/C8 PEG-2000-Cer (por ejemplo, combinado en una relación molar de aproximadamente 31: 40: 25: 4), POPC/DODAP/CS-PEG-2000-Cer (por ejemplo, combinado en una relación molar de aproximadamente 75-87: 3-14: 10) o DSPC/CHOL/DOTAP/C8 PEG-2000-Cer (por ejemplo, combinados en una relación molar de aproximadamente 31: 40: 25: 4). La selección de lípidos catiónicos, lípidos no catiónicos y lípidos modificados con PEG que comprenden el vehículo de transferencia liposomal o la nanopartícula lipídica, así como la relación molar relativa de dichos lípidos entre sí, se basa en las características del lípido seleccionado.), la naturaleza de las células o tejidos diana pretendidos y las características de los ácidos nucleicos a administrar por el vehículo de transferencia liposomal. Las consideraciones adicionales incluyen, por ejemplo, la saturación de la cadena alquílica, así como el tamaño, la carga, el pH, la pKa, la fusogenicidad y la toxicidad del/los lípido(s) seleccionado(s).
[0049] Los vehículos de transferencia de liposomas para uso en la presente invención se pueden preparar mediante diversas técnicas que son actualmente conocidas en la técnica. Las vesículas multilaminares (MLV) se pueden preparar técnicas convencionales, por ejemplo, depositando un lípido seleccionado en la pared interior de un recipiente o recipiente adecuado disolviendo el lípido en un disolvente apropiado, y luego evaporando el disolvente para dejar una película delgada en el interior del recipiente o mediante secado por pulverización. Luego se puede agregar una fase acuosa al recipiente con un movimiento de vortex que da como resultado la formación de MLV. Las vesículas unilaterales (ULV) pueden formarse entonces por homogeneización, sonicación o extrusión de las vesículas multilaminares. Además, las vesículas unilaminares se pueden formar mediante técnicas de eliminación de detergente.
[0050] En determinadas realizaciones de esta invención, las composiciones de la presente invención contienen un vehículo de transferencia en el que el ARNm terapéutico (por ejemplo, ARNm que codifica OTC) se asocia tanto en la superficie del vehículo de transferencia (por ejemplo, un liposoma) y encapsula dentro del mismo vehículo de transferencia. Por ejemplo, durante la preparación de las composiciones de la presente invención, los vehículos de transferencia liposómica catiónica pueden asociarse con el ARNm a través de interacciones electrostáticas con dicho ARNm terapéutico.
[0051] En ciertas realizaciones, las composiciones de la presente invención se pueden cargar con radionúclidos de diagnóstico, materiales fluorescentes u otros materiales que son detectables tanto en aplicaciones in vitro e in vivo. Por ejemplo, los materiales de diagnóstico adecuados para uso en la presente invención pueden incluir Rodaminadioleoilfosfatidiletanolamina (Rh-PE), ARNm de Proteína Fluorescente Verde (ARNm de GFP), ARNm de Renilla Luciferasa y ARNm de Luciferasa de Luciérnaga.
[0052] Durante la preparación de vehículos de transferencia de liposomas, agentes portadores solubles en agua pueden encapsularse en el interior acuoso mediante su inclusión en la solución hidratante, y las moléculas lipófilas pueden incorporarse en la bicapa lipídica por la inclusión en la formulación de lípidos. En el caso de ciertas moléculas (por ejemplo, ácidos nucleicos lipófilos catiónicos o aniónicos), la carga del ácido nucleico en los liposomas preformados se puede llevar a cabo, por ejemplo, mediante los métodos descritos en la patente de EE.UU. Nº 4.946.683. Después de la encapsulación del ácido nucleico, los liposomas pueden procesarse para eliminar el ARNm no encapsulado a través de procesos tales como la cromatografía en gel, la diafiltración o la ultrafiltración. Por ejemplo, si es deseable eliminar el ácido nucleico unido externamente de la superficie de la formulación del vehículo de transferencia liposomal, tales liposomas pueden estar sujetos a una columna de Dietilaminoetilo SEPHACEL.
[0053] Además de ácido nucleico encapsulado, uno o más agentes terapéuticos o de diagnóstico se pueden incluir
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composiciones de la presente invención explotan la capacidad de un sujeto para traducir ARNm preparado exógena
o recombinantemente para producir una proteína o enzima traducida endógenamente, y de ese modo producir (y cuando corresponda excretar) una proteína o enzima funcional. Las proteínas o enzimas expresadas o traducidas también se pueden caracterizar por la inclusión in vivo de modificaciones postraduccionales nativas que a menudo pueden estar ausentes en proteínas o enzimas preparadas de forma recombinante, reduciendo de ese modo adicionalmente la inmunogenicidad de la proteína o enzima traducida.
[0059] La administración de ARNm que codifica una proteína deficiente o enzima evita la necesidad de entregar los ácidos nucleicos a orgánulos específicos dentro de una célula diana (por ejemplo, las mitocondrias). Más bien, tras la transfección de una célula diana y la entrega de los ácidos nucleicos al citoplasma de la célula diana, los contenidos de ARNm de un vehículo de transferencia pueden traducirse y expresarse una proteína o enzima funcional.
[0060] La presente invención también contempla la focalización discriminatoria de las células diana y tejidos tanto por medios de orientación pasivos y activos. El fenómeno de la orientación pasiva explota los patrones de distribución natural de un vehículo de transferencia in vivo sin depender del uso de excipientes adicionales o medios para mejorar el reconocimiento del vehículo de transferencia por las células diana. Por ejemplo, es probable que los vehículos de transferencia que están sujetos a fagocitosis por las células del sistema reticuloendotelial se acumulen en el hígado o el bazo y, en consecuencia, pueden proporcionar medios para dirigir pasivamente la administración de las composiciones a tales células diana.
[0061] Alternativamente, la presente invención contempla la orientación activa, que implica el uso de excipientes adicionales, denominados aquí como "ligandos de orientación" que se pueden unir (ya sea covalentemente o no covalentemente) al vehículo de transferencia para promover la localización de dicha transferencia de vehículo en ciertas células diana o tejidos diana. Por ejemplo, la dirección puede estar mediada por la inclusión de uno o más ligandos de dirección endógenos (por ejemplo, apolipoproteína E) en o sobre el vehículo de transferencia para estimular la distribución a las células o tejidos diana. El reconocimiento del ligando de direccionamiento por los tejidos diana facilita activamente la distribución tisular y la captación celular del vehículo de transferencia y/o su contenido en las células y tejidos diana (por ejemplo, la inclusión de un ligando dirigido a apolipoproteína E en o sobre el vehículo de transferencia alienta el reconocimiento y unión del vehículo de transferencia a receptores de lipoproteína de baja densidad endógenos expresados por hepatocitos). Como se proporciona en este documento, la composición puede comprender un ligando capaz de potenciar la afinidad de la composición a la célula diana. Los ligandos dirigidos se pueden unir a la bicapa externa de la partícula lipídica durante la formulación o la postformulación. Estos métodos son bien conocidos en la técnica. Además, algunas formulaciones de partículas lipídicas pueden emplear polímeros fusogénicos tales como PEAA, hemaglutinina, otros lipopéptidos (véanse las solicitudes de patente de los Estados Unidos números 08/835.281 y 60/083.294) y otras características útiles para la administración in vivo y/o intracelular. En otras algunas realizaciones, las composiciones de la presente invención demuestran eficacias de transfección mejoradas, y/o demuestran selectividad mejorada hacia células o tejidos diana. Por lo tanto, se contemplan composiciones que comprenden uno o más ligandos (por ejemplo, péptidos, aptámeros, oligonucleótidos, una vitamina u otras moléculas) que son capaces de potenciar la afinidad de las composiciones y sus contenidos de ácidos nucleicos por las células o tejidos diana. Los ligandos adecuados pueden unirse opcionalmente o unirse a la superficie del vehículo de transferencia. En algunas realizaciones, el ligando de direccionamiento puede abarcar la superficie de un vehículo de transferencia o estar encapsulado dentro del vehículo de transferencia. Los ligandos adecuados se seleccionan basándose en sus propiedades físicas, químicas
o biológicas (por ejemplo, afinidad selectiva y/o reconocimiento de marcadores o características de la superficie celular diana). Los sitios diana específicos de la célula y su ligando de dirección correspondiente pueden variar ampliamente. Los ligandos de direccionamiento adecuados se seleccionan de modo que se explotan las características únicas de una célula diana, permitiendo así que la composición discrimine entre células diana y no diana. Por ejemplo, las composiciones de la presente invención pueden llevar marcadores superficiales (p. ej., apolipoproteína B o apolipoproteína E) que mejoran selectivamente el reconocimiento o la afinidad a los hepatocitos
(p. ej., mediante el reconocimiento y unión a dichos marcadores de superficie por parte del receptor) Además, se esperaría que el uso de galactosa como ligando de direccionamiento dirigiera las composiciones de la presente invención a hepatocitos parenquimatosos, o alternativamente, se esperaría que el uso de residuos de azúcar que contienen manosa como ligando de direccionamiento dirigiera las composiciones de la presente invención a células endoteliales hepáticas (por ejemplo, manosa que contiene residuos de azúcar que se pueden unir preferentemente al receptor de la asialoglicoproteína presente en los hepatocitos). (Véase Hillery AM, et al. "Drug Delivery and Targeting: For Pharmacists and Pharmaceutical Scientists" (2002) Taylor & Francis, Inc.) La presentación de tales ligandos dirigidos que se han conjugado con restos presentes en el vehículo de transferencia facilita el reconocimiento y la absorción de las composiciones de la presente invención en células y tejidos diana. Los ejemplos de ligandos de direccionamiento adecuados incluyen uno o más péptidos, proteínas, aptámeros, vitaminas y oligonucleótidos.
[0062] Como se usa en el presente documento, el término "sujeto" se refiere a cualquier animal (por ejemplo, un mamífero), incluyendo, pero no limitado a, seres humanos, primates no humanos, roedores, y similares, al que las composiciones de la presente invención son administradas. Típicamente, los términos "sujeto" y "paciente" se usan indistintamente en este documento en referencia a un sujeto humano.
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una placa de 96 pocillos seguido de 20 µL de control de la placa para cada muestra. Por separado, se cargaron 120 µL de reactivo de ensayo de luciferasa (preparado como se describió anteriormente) en cada pocillo de una placa de fondo plano de 96 pocillos. Cada placa se insertó en las cámaras apropiadas utilizando un instrumento Molecular Device Flex Station y se midió la luminiscencia (medida en unidades relativas de luz (RLU)).
Hibridación in situ
Preparación de portaobjetos de tejidos
[0104] La preparación y el análisis de portaobjetos se realizaron de la siguiente manera: cada hígado se congeló a 35ºC de acuerdo con el procedimiento descrito anteriormente. Los hígados congelados se cortaron en secciones de 6 micrómetros y se montaron en portaobjetos de microscopio de vidrio. Antes de la hibridación in situ, las secciones se fijaron en formaldehído al 4% en solución salina tamponada con fosfato (PBS), se trataron con anhídrido trienttanolamina/acético y se lavaron y deshidrataron a través de una serie de soluciones de etanol.
Preparación de la sonda de ARNc
[0105] Plantillas de ADN fueron diseñadas consistiendo de pBSKII + vector conteniendo sitios de restricción de EcoRI y XbaI para la generación de hebras antisentido y sentido, respectivamente. Los transcritos de ARNc se sintetizaron a partir de estas plantillas de ADN (cadenas antisentido y sentido, cada una de 700 pb) con polimerasa ARN T3 y T7, respectivamente. Las plantillas se validaron mediante síntesis de sonda fría de ARN antes de hacer ribosondas con 35S-UTP. Tanto las ribosondas radiomarcadas antisentido como las de sentido se sintetizaron in vitro según el protocolo del fabricante (Ambion) y se marcaron con 35S-UTP (>1.000Ci/mmol).
Hibridación y procedimientos de lavado
[0106] Las secciones se hibridaron durante la noche a 55°C en formamida desionizada, NaCl 0,3 M, Tris-HCl 20 mM (pH 7,4), EDTA 5 mM, Na2HPO410 mM, 10% de sulfato de dextrano, reactivo de Denhardt 1X, 50 µg/ml ARN de levadura total y 50-80,000 cpm/µL 35S sonda marcada de ARNc. Los tejidos se sometieron a un lavado riguroso a 65°C en formamida al 50%, 2X SSC, DTT 10 mM y se lavaron en PBS antes del tratamiento con 20 µg/ml de ARNasa A a 37°C durante 30 minutos. Después de lavados en 2X SSC y 0,1X SSC durante 10 minutos a 37°C, los portaobjetos se deshidrataron y se expusieron a la película de rayos X Kodak BioMaxMR durante 90 minutos y luego se sometieron a autorradiografía en emulsión durante 11 y 24 horas de exposición.
Imágenes de secciones de hígado
[0107] El desarrollo fotográfico se llevó a cabo en Kodak D-19. Las secciones se contratiñeron ligeramente con violeta de cresilo y se analizaron mediante campo claro y microscopio de campo oscuro. Las ribosondas de sentido (control) establecieron el nivel de señal de fondo.
Resultados de bioluminiscencia in vivo
[0108] Los animales fueron inyectados por vía intravenosa con una sola dosis de 200 µg de ARNm encapsulado y se sacrificaron después de cuatro horas. La actividad de la proteína de luciferasa de luciérnaga expresada en hígados y bazos se determinó en un ensayo de bioluminiscencia. Como se demuestra en la FIG. 2, se observó señal detectable sobre la línea de base en cada animal probado. La presencia de una señal luminiscente sobre el fondo infiere la expresión de la proteína luciferasa de luciérnaga a partir del ARNm exógeno. La luminiscencia observada en el hígado se mejoró sobre señales similares observadas en el bazo.
Resultados de la hibridación In situ
[0109] Los estudios de hibridación se llevaron a cabo in situ en hígado tomado de dos animales diferentes de entre el grupo de los ratones tratados con el uso de un vehículo de transferencia ICE: DOPE:DMG-PEG-2000 (preparado como se describe anteriormente) y un hígado de control desde el grupo no tratado de ratones. La autorradiografía de película de rayos X se empleó para la detección de ARNm de luciferasa de luciérnaga optimizado para codones a través de riboondas marcadas con 35S-U. (Véase, Wilcox, J.N. J. Histochem. Cytochem. 41, 1725 -1733 (1993)). FIG. 3 muestra tanto iluminación de campo claro (contratinción de violeta de cresilo) como iluminación de campo oscuro de hígados de control e tratados bajo aumento bajo (2X). El ARNm de luciferasa CO-FF se detectó en hígados tratados (B1 y B2, flechas delgadas) pero no en el hígado control (Ct) cuando se usó la ribosonda antisentido (FIG. 38). Se observó un marcado de ARNm de alto nivel en la banda de tejido marginal hepático (flecha grande). No se detectó señal en ningún hígado cuando se aplicaba la ribosonda de control (sentido) (FIG. 3C).
[0110] Bajo un campo oscuro, la iluminación etiquetada con ARNm de FFL se detectó como puntos brillantes (aumento de 100X) en los hígados de animales inyectados mediante hibridación de una sonda antisentido de ARNm de FFL (FIG. 4A), mientras que el mismo hígado mostró pocos puntos brillantes cuando se usó una sonda de cadena sentido de ARNm de FFF para la hibridación (FIG. 4C). Un hígado de control tomado de un animal que no
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