ES2566508T3 - Oligonucleótidos antisentido dirigidos contra el factor de crecimiento de tejido conjuntivo y usos de los mismos - Google Patents
Oligonucleótidos antisentido dirigidos contra el factor de crecimiento de tejido conjuntivo y usos de los mismos Download PDFInfo
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Abstract
Compuesto que comprende un oligonucleótido modificado que consiste en 12-30 nucleósidos unidos, del que al menos una parte de secuencia de 12 nucleobases es complementaria a los nucleótidos presentes dentro de la región seleccionada de los nucleótidos 1399-1423, 1388-1423 y 1394-1423 de SEQ ID NO: 9, en el que el oligonucleótido modificado comprende: (a) un segmento de separación que consiste en desoxinucleósidos unidos; (b) un segmento de ala en 5' que consiste en nucleósidos modificados unidos; y (c) un segmento de ala en 3' que consiste en nucleósidos modificados unidos; en el que el segmento de separación está situado entre el segmento de ala en 5' y el segmento de ala en 3' y en el que cada nucleósido modificado dentro de cada segmento de ala comprende un azúcar modificado.
Description
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de carbono en 4’ en el que n es 1 ó 2, incluyendo a-L-metilenoxi (4’-CH2-O-2’)-BNA, β-D-metilenoxi (4’-CH2-O-2’)-BNA y etilenoxi (4’-(CH2)2-O-2’)-BNA. Los azúcares modificados bicíclicos también incluyen (6’S)-6’metil-BNA, aminooxi (4’-CH2-O-N(R)-2’)-BNA, oxiamino (4’-CH2-N(R)-O-2’)-BNA en los que R es, independientemente, H, un grupo protector, o alquilo C1-C12. Los LNA también forman dúplex con ADN, ARN o LNA complementarios con altas afinidades térmicas. Los espectros de dicroísmo circular (CD) muestran que los dúplex que implican LNA completamente modificado (especialmente LNA:ARN) se parecen estructuralmente a un dúplex de ARN:ARN de forma A. El examen por resonancia magnética nuclear (RMN) de un dúplex de LNA:ADN confirmó la conformación 3’-endo de un monómero de LNA. También se ha demostrado el reconocimiento de ADN bicatenario lo que sugiere la invasión de cadena mediante LNA. Estudios de secuencias con apareamiento erróneo muestran que los LNA obedecen las reglas de formación de pares de bases de Watson-Crick con selectividad generalmente mejorada en comparación con las cadenas de referencia sin modificar correspondientes.
Los LNA en los que el grupo 2’-hidroxilo está unido al átomo de carbono en 4’ del anillo de azúcar formando así una unió 2’-C,4’-C-oximetileno formando así un resto de azúcar bicíclico. La unión puede ser un grupo metileno (-CH2-)n que forma un puente entre el átomo de oxígeno en 2’ y el átomo de carbono en 4’ en el que n es 1 ó 2 (Singh et al., Chem. Commun., 1998, 4, 455-456). LNA y análogos de LNA muestran estabilidades térmicas de dúplex muy altas con ADN y ARN complementarios (Tf= de +3 a +10ºC), estabilidad frente a degradación 3’-exonucleolítica y buenas propiedades de solubilidad. Otros grupos de puente preferidos incluyen el puente 2’-desoxi-2’-CH2OCH2-4’. Los LNA y la preparación de los mismos se describen en las solicitudes de patente internacional publicadas n.os WO 98/39352 y WO 99/14226.
Otras modificaciones preferidas incluyen 2’-metoxilo (2’-O-CH3), 2’-aminopropoxilo (2’-OCH2CH2CH2NH2), 2’-alilo (2’-CH2-CH=CH2), 2’-O-alilo (2’-O-CH2-CH=CH2) y 2’-fluoro (2’-F). La modificación en 2’ puede estar en la posición arabino (hacia arriba) o la posición ribo (hacia abajo). Una modificación arabino en 2’ preferida es 2’-F. También pueden prepararse modificaciones similares en otras posiciones en el oligonucleótido, particularmente la posición 3’ del azúcar en el nucleótido 3’-terminal o en oligonucleótidos con unión 2’-5’ y la posición 5’ del nucleótido 5’-terminal. Los oligonucleótidos también pueden tener sustitutos o compuestos miméticos de azúcar (algunas veces denominados análogos de ADN) tales como restos ciclobutilo en lugar del pentofuranosil-azúcar. Las patentes estadounidenses representativas que enseñan la preparación de tales estructuras de azúcar modificadas incluyen, pero no se limitan a, las patentes estadounidenses n.os: 4.981.957; 5.118.800; 5.319.080; 5.359.044; 5.393.878; 5.446.137; 5.466.786; 5.514.785; 5.519.134; 5.567.811; 5.576.427; 5.591.722; 5.597.909; 5.610.300; 5.627.053; 5.639.873; 5.646.265; 5.658.873; 5.670.633; 5.792.747; y 5.700.920, algunas de las cuales son de titularidad conjunta con la presente solicitud. En determinadas realizaciones, los nucleósidos se modifican mediante sustitución del anillo de ribosilo por un sistema cíclico sustituto tal como un anillo de morfolino, un anillo de ciclohexenilo, un anillo de ciclohexilo o un anillo de tetrahidropiranilo tal como uno que tiene una de las fórmulas:
En la técnica también se conocen muchos otros sistemas cíclicos sustitutos de azúcar biciclos y triciclos que pueden usarse para modificar nucleósidos para su incorporación en compuestos antisentido (véase por ejemplo el artículo de revisión: Leumann, Christian J.). Tales sistemas cíclicos pueden experimentar diversas sustituciones adicionales para potenciar la actividad.
En una realización de la invención, el compuesto que comprende al menos un nucleósido modificado con tetrahidropirano en el que un anillo de tetrahidropirano sustituye al anillo de furanosa.
En otra realización de la invención, en la que cada uno del al menos un nucleósido modificado con tetrahidropirano tiene la estructura:
en la que Bx es un resto de base heterocíclica opcionalmente protegida. Nucleobases modificadas Los oligonucleótidos también pueden incluir modificaciones o sustituciones de nucleobases (con frecuencia
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US19012108P | 2008-08-25 | 2008-08-25 | |
US190121P | 2008-08-25 | ||
PCT/US2009/054973 WO2010042281A2 (en) | 2008-08-25 | 2009-08-25 | Antisense oligonucleotides directed against connective tissue growth factor and uses thereof |
Publications (1)
Publication Number | Publication Date |
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ES2566508T3 true ES2566508T3 (es) | 2016-04-13 |
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Application Number | Title | Priority Date | Filing Date |
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ES09819622.3T Active ES2566508T3 (es) | 2008-08-25 | 2009-08-25 | Oligonucleótidos antisentido dirigidos contra el factor de crecimiento de tejido conjuntivo y usos de los mismos |
Country Status (20)
Country | Link |
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US (6) | US8252762B2 (es) |
EP (2) | EP3081648A1 (es) |
JP (5) | JP5420668B2 (es) |
KR (2) | KR101877698B1 (es) |
CN (2) | CN107083386A (es) |
AU (2) | AU2009275387B2 (es) |
BR (1) | BRPI0912923A8 (es) |
CA (1) | CA2733262C (es) |
CO (1) | CO6341577A2 (es) |
DK (1) | DK2331141T3 (es) |
EA (1) | EA022207B1 (es) |
ES (1) | ES2566508T3 (es) |
GB (1) | GB2465902B (es) |
HK (2) | HK1144908A1 (es) |
IL (3) | IL211230A (es) |
MX (2) | MX2011002143A (es) |
NZ (2) | NZ591416A (es) |
SG (1) | SG196769A1 (es) |
WO (1) | WO2010042281A2 (es) |
ZA (1) | ZA201101549B (es) |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
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CA2655993A1 (en) * | 2005-09-30 | 2007-07-05 | The Regents Of The University Of California | Satb1: a determinant of morphogenesis and tumor metastatis |
US10131904B2 (en) | 2008-02-11 | 2018-11-20 | Rxi Pharmaceuticals Corporation | Modified RNAi polynucleotides and uses thereof |
WO2010008582A2 (en) | 2008-07-18 | 2010-01-21 | Rxi Pharmaceuticals Corporation | Phagocytic cell drug delivery system |
US8946172B2 (en) | 2008-08-25 | 2015-02-03 | Excaliard Pharmaceuticals, Inc. | Method for reducing scarring during wound healing using antisense compounds directed to CTGF |
EP3081648A1 (en) | 2008-08-25 | 2016-10-19 | Excaliard Pharmaceuticals, Inc. | Antisense oligonucleotides directed against connective tissue growth factor and uses thereof |
JP2012502991A (ja) | 2008-09-22 | 2012-02-02 | アールエックスアイ ファーマシューティカルズ コーポレーション | 皮膚適用におけるrna干渉 |
WO2010059226A2 (en) | 2008-11-19 | 2010-05-27 | Rxi Pharmaceuticals Corporation | Inhibition of map4k4 through rnai |
US9493774B2 (en) | 2009-01-05 | 2016-11-15 | Rxi Pharmaceuticals Corporation | Inhibition of PCSK9 through RNAi |
WO2010090762A1 (en) | 2009-02-04 | 2010-08-12 | Rxi Pharmaceuticals Corporation | Rna duplexes with single stranded phosphorothioate nucleotide regions for additional functionality |
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