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RU2019111696A - Композиции и способы ингибирования экспрессии гена alas1 - Google Patents

Композиции и способы ингибирования экспрессии гена alas1 Download PDF

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RU2019111696A
RU2019111696A RU2019111696A RU2019111696A RU2019111696A RU 2019111696 A RU2019111696 A RU 2019111696A RU 2019111696 A RU2019111696 A RU 2019111696A RU 2019111696 A RU2019111696 A RU 2019111696A RU 2019111696 A RU2019111696 A RU 2019111696A
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dnrna
cell
subject
alas1
porphyrin
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RU2019111696A
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RU2842959C2 (ru
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Брайан Беттенкорт
Кевин Фитцжеральд
Уилльям Куэрбс
Макико Ясуда
Роберт Дж. ДЕСНИК
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Элнилэм Фармасьютикалз, Инк.
Икан Скул Оф Медсин Эт Маунт Синай
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Claims (35)

1. Двунитевая рибонуклеиновая кислота (днРНК) для ингибирования экспрессии ALAS1, содержащая:
антисмысловую нить, которая содержит полседовательность SEQ ID NO: 1296;
смысловую нить, содержащую по меньшей мере 15 непрерывно следующих друг за другом нуклеотидов из SEQ ID NO: 1295; и
область дуплекса длиной из 15-30 пар оснований.
2. днРНК по п. 1, где указанная днРНК содержит по меньшей мере один модифицированный нуклеотид.
3. днРНК по п. 1, где каждая из смысловой нити и антисмысловой нити имеет длину из 19-24 нуклеотидов.
4. днРНК по п. 1, где по меньшей мере одна смысловая нить содержит 3' из 1 нуклеотида.
5. днРНК по п. 4, где 3'липкий конец имеет длину из 2 нуклеотидов.
6. днРНК по п. 1, дополнительно содержащий лиганд.
7. днРНК по п. 6, где указанный лиганд представляет собой лиганд GalNAc.
8. Выделенная клетка, содержащая днРНК по п. 1.
9. Фармацевтическая композиция для ингибирования экспрессии гена ALAS1, где композиция содержит днРНК по п. 1.
10. Способ ингибирования экспрессии ALAS1 в клетке, где способ включает:
введение в клетку днРНК по п.1, и
поддержание клетки со стадии (a) в течение периода времени, достаточного для получения распада транскрипта мРНК гена ALAS1 и, тем самым, ингибирования экспрессии гена ALAS1 в клетке.
11. Способ лечения расстройства, связанного с экспрессией ALAS1, включающий в себя введение субъекту, нуждающемуся в таком лечении, терапевтически эффективного количества днРНК по п. 1.
12. Способ по п. 11, в котором субъект подвергается риску развития порфирии, или у него диагностирована порфирия.
13. Способ по п. 11, в котором днРНК вводят до, во время или после острого приступа порфирии.
14. Способ по п. 11, в котором способ снижает уровень порфирина или предшественника порфирина у субъекта.
15. Способ снижения уровня порфирина или предшественника порфирина в клетке, включающий в себя осуществление контакта клетки с днРНК по п. 1, в количестве, эффективном для снижения уровня порфирина или предшественника порфирина в клетке.
16. Вектор, кодирующий по меньшей мере одну нить днРНК по п. 1.
17. Выделенная клетка, содержащая вектор по п. 16.
18. Способ по п. 11, где способ
ослабляет симптом, ассоциированный с расстройством, связанным с ALAS1 (например, порфирией),
ингибирует экспрессию ALAS1 у субъекта,
снижает уровень предшественника порфирина или порфирина у субъекта,
снижает частоту острых приступов симптомов, ассоциированных с порфирией у субъекта, или
снижает частоту возникновения острых приступов симптомов, ассоциированных с порфирией у субъекта в том случае, когда субъект подвергается воздействию провоцирующего фактора.
19. днРНК по п. 7, где лиганд GalNAc присоединен к 3' концу смысловой нити.
20. днРНК по п. 1, где по меньшей мере один модифицированный нуклеотид выбран из 2'-O-метил модифицированного нуклеотида и 2'-фтор модифицированного нуклеотида.
21. днРНК по п. 20, где лиганд GalNAc присоединен к 3'концу смысловой нити через линкер.
22. днРНК по п. 6, где лиганд GalNAc представляет собой
Figure 00000001
.
23. днРНК по п. 22, где лиганд и линкер имеет структуру:
Figure 00000002
.
RU2019111696A 2012-04-10 2013-04-10 Композиции и способы ингибирования экспрессии гена alas1 RU2842959C2 (ru)

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