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RU2008147665A - МАЛАЯ ИНТЕРФЕРИРУЮЩАЯ РИБОНУКЛЕИНОВАЯ КИСЛОТА (миРНК) ДЛЯ ПЕРОРАЛЬНОГО ВВЕДЕНИЯ - Google Patents

МАЛАЯ ИНТЕРФЕРИРУЮЩАЯ РИБОНУКЛЕИНОВАЯ КИСЛОТА (миРНК) ДЛЯ ПЕРОРАЛЬНОГО ВВЕДЕНИЯ Download PDF

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Publication number
RU2008147665A
RU2008147665A RU2008147665/13A RU2008147665A RU2008147665A RU 2008147665 A RU2008147665 A RU 2008147665A RU 2008147665/13 A RU2008147665/13 A RU 2008147665/13A RU 2008147665 A RU2008147665 A RU 2008147665A RU 2008147665 A RU2008147665 A RU 2008147665A
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RU
Russia
Prior art keywords
sirna
aryl
alkyl
sirna according
nucleotides
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RU2008147665/13A
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English (en)
Inventor
Франсуа Жан-Шарль НАТТ (FR)
Франсуа Жан-Шарль НАТТ
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Новартис АГ (CH)
Новартис Аг
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Publication of RU2008147665A publication Critical patent/RU2008147665A/ru

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Abstract

1. Малая интерферирующая рибонуклеиновая кислота (миРНК) для перорального введения, включающая две отдельные нити РНК, комплементарные друг другу на протяжении по меньшей мере 15 нуклеотидов, причем каждая нить состоит из 49 нуклеотидов или меньше, и по меньшей мере одна из нитей содержит по меньшей мере одну химическую модификацию. ! 2. миРНК по п.1, включающая по меньшей мере один модифицированный нуклеотид. ! 3. миРНК по п.1, включающая по меньшей мере один кэп 3'-конца. ! 4. миРНК по п.2, в которой указанный модифицированный нуклеотид, выбран из числа 2'-алкоксирибонуклеотида, 2'-алкоксиалкоксирибонуклеотида, рибонуклеотида замкнутой нуклеиновой кислоты (ЗНК), 2'-фторрибонуклеотида, нуклеотида морфолино. ! 5. миРНК по п.2, в которой указанный модифицированный нуклеотид выбран из числа нуклеотидов, имеющих модифицированную межнуклеозидную связь, которая выбрана из фосфоротиоатной, фосфородитиоатной, фосфорамидатной, боранофосфоноатной и амидной связи. ! 6. миРНК по п.1, в которой указанные две цепи РНК полностью комплементарны друг другу. ! 7. миРНК по п.1, включающая выступ из 1-6 нуклеотидов, выступающий по меньшей мере с одного 5'-конца или 3'-конца. ! 8. миРНК по п.3, в которой указанный по меньшей мере один 3'-кэп, если он имеется, является частью молекулы, соединенной с 3'-концом через 3'-углерод, и выбран из числа соединений формулы I: ! ! в которой ! X обозначает О или S ! R1 и R2 независимо являются ОН, NH2, SH, алкилом, арилом, алкил-арилом, арил-алкилом, причем алкил, арил, алкил-арил, арил-алкил могут быть замещены дополнительными гетероатомами и функциональными группами, предпочтительно гетероатомом, выбранным из группы N, О или S, или фу�

Claims (23)

1. Малая интерферирующая рибонуклеиновая кислота (миРНК) для перорального введения, включающая две отдельные нити РНК, комплементарные друг другу на протяжении по меньшей мере 15 нуклеотидов, причем каждая нить состоит из 49 нуклеотидов или меньше, и по меньшей мере одна из нитей содержит по меньшей мере одну химическую модификацию.
2. миРНК по п.1, включающая по меньшей мере один модифицированный нуклеотид.
3. миРНК по п.1, включающая по меньшей мере один кэп 3'-конца.
4. миРНК по п.2, в которой указанный модифицированный нуклеотид, выбран из числа 2'-алкоксирибонуклеотида, 2'-алкоксиалкоксирибонуклеотида, рибонуклеотида замкнутой нуклеиновой кислоты (ЗНК), 2'-фторрибонуклеотида, нуклеотида морфолино.
5. миРНК по п.2, в которой указанный модифицированный нуклеотид выбран из числа нуклеотидов, имеющих модифицированную межнуклеозидную связь, которая выбрана из фосфоротиоатной, фосфородитиоатной, фосфорамидатной, боранофосфоноатной и амидной связи.
6. миРНК по п.1, в которой указанные две цепи РНК полностью комплементарны друг другу.
7. миРНК по п.1, включающая выступ из 1-6 нуклеотидов, выступающий по меньшей мере с одного 5'-конца или 3'-конца.
8. миРНК по п.3, в которой указанный по меньшей мере один 3'-кэп, если он имеется, является частью молекулы, соединенной с 3'-концом через 3'-углерод, и выбран из числа соединений формулы I:
Figure 00000001
в которой
X обозначает О или S
R1 и R2 независимо являются ОН, NH2, SH, алкилом, арилом, алкил-арилом, арил-алкилом, причем алкил, арил, алкил-арил, арил-алкил могут быть замещены дополнительными гетероатомами и функциональными группами, предпочтительно гетероатомом, выбранным из группы N, О или S, или функциональной группой, выбранной из группы ОН, NH2, SH, карбоновой кислоты или сложного эфира,
или R1 и R2 могут иметь формулу Y-Z, в которой Y обозначает О, N, S, a Z обозначает Н, алкил, арил, алкил-арил, арил-алкил, причем алкил, арил, алкил-арил, арил-алкил могут быть замещены дополнительными гетероатомами, предпочтительно гетероатомом, выбранным из группы N, О или S.
9. миРНК по п.1, в которой по меньшей мере одна цепь комплементарна на протяжении по меньшей мере 15 нуклеотидов иРНК или пре-иРНК VEGFR-1, VEGFR-2, VEGFR3, Tie2, bFGFR, IL8RA, IL8RB, Fas или IGF2R.
10. миРНК по п.1, в которой по меньшей мере одна цепь включает последовательность, выбранную из последовательностей SEQ ID NO 1-900.
11. миРНК, выбранная из группы, состоящей из последовательностей SEQ ID NO 901-930.
12. миРНК по одному из пп.1-11, проявляющая стабильность при стандартном исследовании воздействия желудочного сока, которая выше, чем у немодифицированной миРНК с той же нуклеотидной последовательностью.
13. миРНК по одному из пп.1-11, проявляющая стабильность при стандартном исследовании воздействия желудочного сока, которая выше или равна 50% после экспозиции 30 мин.
14. миРНК по одному из пп.1-11, проявляющая стабильность при стандартном исследовании воздействия сыворотки, которая выше, чем у немодифицированной миРНК.
15. миРНК по одному из пп.1-11, проявляющая стабильность при стандартном исследовании воздействия сыворотки, которая выше или равна 50% после экспозиции 30 мин.
16. миРНК по одному из пп.1-11, проявляющая стабильность при стандартном исследовании воздействия промывных вод кишечника, которая выше, чем у немодифицированной миРНК.
17. миРНК по одному из пп.1-11, обладающая повышенной пероральной биодоступностью по сравнению с немодифицированной миРНК той же нуклеотидной последовательности.
18. Фармацевтическая композиция, включающая миРНК по одному из пп.1-11.
19. миРНК по одному из пп.1-11 для применения в качестве лекарственного средства.
20. Применение миРНК для перорального введения, причем указанная миРНК выбирается из группы, включающей SEQ ID NO 1-930 и/или указанная миРНК включает две отдельные нити, которые комплементарны друг другу на протяжении по меньшей мере 15 нуклеотидов, причем каждая нить состоит из 49 нуклеотидов или меньше и где по меньшей мере одна из нитей содержит по меньшей мере одну модификацию, причем миРНК используется для приготовления лекарственного средства для лечения ангиогенного расстройства.
21. Применение по п.20, в котором ген, на который нацеливается миРНК, экспрессируется на клетках эндотелия.
22. Применение по п.21, в котором ген, на который нацеливается миРНК, выбран из группы, состоящей из: VEGFR-1 (база данных GenBank, номер в каталоге AF06365), VEGFR-2 (база данных GenBank, номер в каталоге AF063658), VEGFR-3 (база данных GenBank, номер в каталоге NM_002020), Tie2 (ТЕК) (база данных GenBank, номер в каталоге NM_000459), bFGFR (база данных GenBank, номер в каталоге М60485), IL8RA (база данных GenBank, номер в каталоге L19591), IL8RB (база данных GenBank, номер в каталоге L19593), Fas (база данных GenBank, номер в каталоге Х89101), IGF2R (база данных GenBank, номер в каталоге NM_000876).
23. Применение миРНК по одному из пп.1-11 для подавления ангиогенного процесса in vitro.
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