RU2014101627A - КОМПОЗИЦИИ иРНК ДЛЯ СХОДНОГО С АНГИОПОЭТИНОМ 3(ANGPTL3) БЕЛКА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ - Google Patents

КОМПОЗИЦИИ иРНК ДЛЯ СХОДНОГО С АНГИОПОЭТИНОМ 3(ANGPTL3) БЕЛКА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ Download PDF

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RU2014101627A
RU2014101627A RU2014101627/10A RU2014101627A RU2014101627A RU 2014101627 A RU2014101627 A RU 2014101627A RU 2014101627/10 A RU2014101627/10 A RU 2014101627/10A RU 2014101627 A RU2014101627 A RU 2014101627A RU 2014101627 A RU2014101627 A RU 2014101627A
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Брайан БЕТТЕНКОРТ
Уилльям КУЭРБС
Кевин Фитцжеральд
Мария Франк-Каменетски
Стюарт Милстейн
Светлана ШУЛЬГА-МОРСКАЯ
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Элнилэм Фармасьютикалз
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Abstract

1. Двухцепочечная рибонуклеиновая кислота (дцРНК) для ингибирования экспрессии ANGPTL3, где указанная дцРНК содержит смысловую цепь и антисмысловую цепь, где указанная смысловая цепь содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от нуклеотидной последовательности SEQ ID NO:1, и указанная антисмысловая цепь содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от нуклеотидной последовательности SEQ ID NO:5.2. Двухцепочечная рибонуклеиновая кислота (дцРНК) для ингибирования экспрессии ANGPTL3, где указанная дцРНК содержит смысловую цепь и антисмысловую цепь, где антисмысловая цепь содержит участок комплементарности, который содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от любой из антисмысловых последовательностей, перечисленных в таблицах 2, 3, 7, 8, 9 и 10.3. дцРНК по п. 2, где смысловая и антисмысловая цепи содержат последовательности, выбранные из группы, состоящей из AD-52981.1, AD-53063.1, AD-53001.1, AD-53015.1, AD-52986.1, AD-52953.1, AD-53024.1, AD-53033.1, AD-53030.1, AD-53080.1, AD-53073.1, AD-53132.1, AD-52983.1, AD-52954.1, AD-52961.1, AD-52994.1, AD-52970.1, AD-53075.1, AD-53147.1, AD-53077.1 из таблиц 7 и 8.4. дцРНК по п. 1 или 2, где указанная дцРНК содержит по меньшей мере один модифицированный нуклеотид.5. дцРНК по п. 4, где по меньшей мере один из указанных модифицированных нуклеотидов выбран из группы, состоящей из 2′-O-метилмодифицированного нуклеотида, нуклеотида, содержащего 5′-тиофосфатную группу, и концевого нуклеотида, связанного с производным холестерила или группой бисдециламида додекановой кислоты.6. дцРНК по п. 4, где указанный модифицированный нуклеотид выбран из группы, состоящей из 2′-дезокси-

Claims (40)

1. Двухцепочечная рибонуклеиновая кислота (дцРНК) для ингибирования экспрессии ANGPTL3, где указанная дцРНК содержит смысловую цепь и антисмысловую цепь, где указанная смысловая цепь содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от нуклеотидной последовательности SEQ ID NO:1, и указанная антисмысловая цепь содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от нуклеотидной последовательности SEQ ID NO:5.
2. Двухцепочечная рибонуклеиновая кислота (дцРНК) для ингибирования экспрессии ANGPTL3, где указанная дцРНК содержит смысловую цепь и антисмысловую цепь, где антисмысловая цепь содержит участок комплементарности, который содержит по меньшей мере 15 смежных нуклеотидов, отличающихся не более чем на 3 нуклеотида от любой из антисмысловых последовательностей, перечисленных в таблицах 2, 3, 7, 8, 9 и 10.
3. дцРНК по п. 2, где смысловая и антисмысловая цепи содержат последовательности, выбранные из группы, состоящей из AD-52981.1, AD-53063.1, AD-53001.1, AD-53015.1, AD-52986.1, AD-52953.1, AD-53024.1, AD-53033.1, AD-53030.1, AD-53080.1, AD-53073.1, AD-53132.1, AD-52983.1, AD-52954.1, AD-52961.1, AD-52994.1, AD-52970.1, AD-53075.1, AD-53147.1, AD-53077.1 из таблиц 7 и 8.
4. дцРНК по п. 1 или 2, где указанная дцРНК содержит по меньшей мере один модифицированный нуклеотид.
5. дцРНК по п. 4, где по меньшей мере один из указанных модифицированных нуклеотидов выбран из группы, состоящей из 2′-O-метилмодифицированного нуклеотида, нуклеотида, содержащего 5′-тиофосфатную группу, и концевого нуклеотида, связанного с производным холестерила или группой бисдециламида додекановой кислоты.
6. дцРНК по п. 4, где указанный модифицированный нуклеотид выбран из группы, состоящей из 2′-дезокси-2′-фтормодифицированного нуклеотида, 2′-дезоксимодифицированного нуклеотида, замкнутого нуклеотида, абазического нуклеотида, 2′-аминомодифицированного нуклеотида, 2′-алкилмодифицированного нуклеотида, нуклеотида морфолино, фосфорамидата и неприродного основания, содержащего нуклеотид.
7. дцРНК по п. 2, где длина участка комплементарности составляет по меньшей мере 17 нуклеотидов в длину.
8. дцРНК по п. 2, где длина участка комплементарности составляет от 19 до 21 нуклеотидов.
9. дцРНК по п. 8, где длина участка комплементарности составляет 19 нуклеотидов.
10. дцРНК по п. 1 или 2, где длина каждой цепи составляет не более 30 нуклеотидов в длину.
11. дцРНК по п. 1 или 2, где по меньшей мере одна цепь содержит 3′-липкий конец по меньшей мере 1 нуклеотида.
12. дцРНК по п. 1 или 2, где по меньшей мере одна цепь содержит 3′-липкий конец по меньшей мере из 2 нуклеотидов.
13. дцРНК по п. 1 или 2, дополнительно содержащая лиганд.
14. дцРНК по п. 13, где лиганд конъюгирован с 3′-концом смысловой цепи дцРНК.
15. дцРНК по п. 13, где лиганд представляет собой производное N-ацетилгалактозамина (GalNAc).
16. дцРНК по п. 15, где лиганд представляет собой
Figure 00000001
17. дцРНК по п. 2, где участок комплементарности состоит из одной из антисмысловых последовательностей из таблиц 2, 3, 7, 8, 9 и 10.
18. дцРНК по п. 1 или 2, где дцРНК содержит смысловую цепь, состоящую из последовательности смысловой цепи, выбранной из последовательности из таблиц 2, 3, 9 и 10, и антисмысловой цепи, состоящей из антисмысловой последовательности, выбранной из последовательности из таблиц 2, 3, 7, 8, 9 и 10.
19. Клетка, содержащая дцРНК по п. 1 или 2.
20. Вектор, кодирующий по меньшей мере одну цепь дцРНК, где указанная дцРНК содержит участок комплементарности по меньшей мере к части мРНК, кодирующей ANGPTL3, где длина указанной дцРНК составляет 30 пар оснований или менее, и где указанная дцРНК направлена на расщепление указанной мРНК.
21. Вектор по п. 20, где длина участка комплементарности составляет по меньшей мере 15 нуклеотидов.
22. Вектор по п. 20, где длина участка комплементарности составляет от 19 до 21 нуклеотида.
23. Клетка, содержащая вектор по п. 20.
24. Фармацевтическая композиция для ингибирования экспрессии гена ANGPTL3, содержащая дцРНК по п. 1 или 2 или вектор по п. 20.
25. Фармацевтическая композиция по п. 24, дополнительно содержащая липидный состав.
26. Фармацевтическая композиция по п. 24, где липидный состав содержит SNALP или XTC.
27. Фармацевтическая композиция по п. 24, где липидный состав содержит MC3.
28. Способ ингибирования экспрессии ANGPTL3 в клетке, где способ включает:
a) приведение клетки в контакт с дцРНК по п. 1 или 2 или вектором по п. 20 и
b) поддержание клетки, полученной на стадии a) в течение периода времени, достаточного для получения деградации транскрипта мРНК гена ANGPTL3, таким образом ингибируя экспрессию гена ANGPTL3 в клетке.
29. Способ по п. 28, где указанная клетка находится у индивидуума.
30. Способ по п. 29, где индивидуум представляет собой человека.
31. Способ по п. 30, где являющийся человеком индивидуум страдает от нарушения метаболизма липидов.
32. Способ по п. 31, где нарушение метаболизма липидов представляет собой гиперлипидемию или гипертриглицеридемию.
33. Способ по любому из пп. 28-32, где экспрессию ANGPTL3 ингибируют по меньшей мере приблизительно на 30%.
34. Способ лечения индивидуума с нарушением, на которое окажет благоприятное действие снижение экспрессии ANGPTL3, включающий введение индивидууму терапевтически эффективного количества дцРНК по п. 1, или 2, или вектора по п. 20, таким образом, проводя лечение указанного индивидуума.
35. Способ по п. 34, где нарушение представляет собой нарушение метаболизма липидов.
36. Способ по п. 35, где нарушение метаболизма липидов представляет собой гиперлипидемию или гипертриглицеридемию.
37. Способ по п. 34, где введение дцРНК индивидууму вызывает снижение одного или более липидов сыворотки и/или снижение накопления белка ANGPTL3.
38. Способ по п. 34, где дцРНК вводят в дозе приблизительно от 0,01 мг/кг приблизительно до 10 мг/кг или приблизительно от 5 мг/кг приблизительно до 50 мг/кг.
39. Способ ингибирования экспрессии ANGPTL3 у индивидуума, где способ включает введение указанному индивидууму терапевтически эффективного количества дцРНК по п. 1, или 2, или вектора по п. 20, таким образом, ингибируя экспрессию ANGPTL3 у указанного индивидуума.
40. Способ по п. 39, где дцРНК вводят указанному индивидууму в дозе приблизительно от 0,01 мг/кг приблизительно до 10 мг/кг или приблизительно от 5 мг/кг приблизительно до 50 мг/кг.
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