RU2019127316A - Рнк-направляемая инженерия генома человека - Google Patents

Рнк-направляемая инженерия генома человека Download PDF

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RU2019127316A
RU2019127316A RU2019127316A RU2019127316A RU2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A
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sequence
nucleic acid
rna
rna guide
guide
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RU2766685C2 (ru
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Джордж М. ЧЁРЧ
Прашант МАЛИ
Лухан ЯНГ
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Президент Энд Фэллоуз Оф Харвард Коллидж
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Claims (39)

1. Направляющая РНК, предназначенная для изменения эукариотической клетки, содержащая направляющую последовательность, комплементарную целевой последовательности нуклеиновой кислоты и каркасной последовательности, присоединенной к направляющей последовательности, и каркасную последовательность, причем направляющая РНК содержит от около 100 до около 250 нуклеотидов.
2. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК содержит около 100 нуклеотидов.
3. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК.
4. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК, обладающий вторичной структурой, включающей первую шпильку, соединенную со спейсерной последовательностью, и вторую 3’-шпильку.
5. Направляющая РНК по п. 1, отличающаяся тем, что каркасная последовательность включает следующую последовательность нуклеиновой кислоты GUUUUAGAGCUAGAAA UAGCAAGUUAAAAUAA GGCUAGUCCGUUAUCA ACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO:46).
6. Направляющая РНК по п. 1, отличающаяся тем, что к 3’-концу каркасной последовательности присоединена последовательность поли-U.
7. Направляющая РНК по п. 1, отличающаяся тем, что последовательность поли-U UUUU присоединена к 3’-концу каркасной последовательности.
8. Сконструированная последовательность нуклеиновой кислоты, содержащая нуклеотидную последовательность, кодирующую последовательность направляющей РНК по п. 1.
9. Сконструированная последовательность нуклеиновой кислоты по п. 8, дополнительно включающая регуляторный элемент, способный к функционированию в эукариотической клетке, функционально связанный с нуклеотидной последовательностью, кодирующей последовательность направляющей РНК по п. 1.
10. Сконструированная последовательность нуклеиновой кислоты по п. 9, в которой регуляторный элемент представляет собой промотер U6 полимеразы III человека.
11. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота, кодирующая белок Cas9, модифицированный белок Cas9 или гомолог белка Cas9.
12. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая сигнал ядерной локализации.
13. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 12, в которой сигнал ядерной локализации представляет собой С-концевой сигнал ядерной локализации.
14. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 13, в которой сигнал ядерной локализации представляет собой С-концевой сигнал ядерной локализации SV40.
15. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая функционально присоединенный к ней регуляторный элемент, способный функционировать в эукариотической клетке.
16. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 15, в которой регуляторный элемент представляет собой промотер U6 полимеразы III человека.
17. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая SEQ ID NO:22.
18. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, кодирующая белок Cas9-нуклеазы-нуль, включающий присоединенный к нему
a) домен активации или подавления транскрипции;
b) FokI-нуклеазный домен;
c) флуоресцентный белок,
d) связывающийся с белками органический флуорофор, связывающийся с нуклеиновыми кислотами органический флуорофор, квантовую точку, молекулярный маяк, эхо-зонд или домен мультивалентного лиганд-связывающего белка, отличного от флуоресцентных молекул, таких как связывающихся с белками или нуклеиновыми кислотами органических флуорофоров, квантовых точек, молекулярных маяков, эхо-зондов или заменителей молекулярных маяков; или
e) мультивалентные лиганд-связывающие белки.
19. Система редактирования генома, направляемая РНК, содержащая
(1) последовательность направляющей РНК или последовательность первой нуклеиновой кислоты, кодирующей последовательность направляющей РНК, и
(2) фермент Cas, который образует комплекс с последовательностью направляющей РНК, или последовательность второй нуклеиновой кислоты, кодирующей фермент Cas,
причем последовательность направляющей РНК содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты и связывающуюся с целевой последовательностью нуклеиновой кислоты, и где направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК, содержащий от около 100 до около 250 нуклеотидов.
20. Эукариотическая клетка, включающая систему редактирования генома, направляемая РНК, содержащую
(1) последовательность направляющей РНК или последовательность первой нуклеиновой кислоты, кодирующей последовательность направляющей РНК, и
(2) фермент Cas, который образует комплекс с последовательностью направляющей РНК, или последовательность второй нуклеиновой кислоты, кодирующей фермент Cas,
где последовательность направляющей РНК содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты, которая связывается с целевой последовательностью нуклеиновой кислоты,
где последовательность направляющей РНК представляет собой слитый транскрипт crРНК-tracrРНК, включающий от около 100 нуклеотидов до около 250 нуклеотидов.
21. Эукариотическая клетка по п.20, которая представляет собой дрожжевую клетку, растительную клетку, клетку млекопитающего или клетку человека.
22. Эукариотическая клетка по п.20, где эукариотическая клетка представляет собой стволовую клетку.
23. Эукариотическая клетка по п.20, где эукариотическая клетка представляет собой индуцированную плюрипотентную стволовую клетку человека.
24. Вирус, включающий нуклеиновую кислоту, кодирующую последовательность направляющей РНК, которая содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты, которая связывается с целевой последовательностью нуклеиновой кислоты, где последовательность направляющей РНК представляет собой слитый транскрипт crРНК-tracrРНК, включающий от около 100 нуклеотидов до около 250 нуклеотидов.
25. Вирус по п.24, где вирус представляет собой аденоассоциированный вирус.
26. Вирус, содержащий оптимизированную с учетом использования кодонов человека нуклеиновую кислоту, кодирующую белок Cas9, модифицированный белок Cas9 или гомолог белка Cas9.
27. Вирус по п.26, где вирус представляет собой аденоассоциированный вирус.
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