RU2015128098A - Конструирование систем, способы и оптимизированные направляющие композиции для манипуляции с последовательностями - Google Patents

Конструирование систем, способы и оптимизированные направляющие композиции для манипуляции с последовательностями Download PDF

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RU2015128098A
RU2015128098A RU2015128098A RU2015128098A RU2015128098A RU 2015128098 A RU2015128098 A RU 2015128098A RU 2015128098 A RU2015128098 A RU 2015128098A RU 2015128098 A RU2015128098 A RU 2015128098A RU 2015128098 A RU2015128098 A RU 2015128098A
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crispr
sequence
chirna
tracr
crispr enzyme
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RU2015128098A
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RU2015128098A3 (ru
RU2701850C2 (ru
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Фэн ЧЖАН
Лэ ЦУН
Патрик ХСЮ
Фэй РАН
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Те Брод Инститьют, Инк.
Массачусетс Инститьют Оф Текнолоджи
Президент Энд Феллоуз Оф Харвард Коллидж
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Claims (97)

1. Не встречающаяся в природе или сконструированная композиция, содержащая:
A) полинуклеотидную последовательность химерной РНК (chiRNA) системы CRISPR-CAS, где полинуклеотидная последовательность содержит
(a) направляющую последовательность, способную гибридизироваться с целевой последовательностью в эукариотической клетке,
(b) парную tracr-последовательность и
(c) tracr-последовательность,
где (а), (b) и (с) расположены в 5'-3' ориентации,
где при транскрипции парная tracr-последовательность гибридизируется с tracr-последовательностью, а направляющая последовательность управляет специфичным к последовательности связыванием комплекса CRISPR с целевой последовательностью,
где комплекс CRISPR содержит фермент CRISPR, образующий комплекс с (1) направляющей последовательностью, которая гибридизируется с целевой последовательностью, и (2) парной tracr-последовательностью, которая гибридизируется с tracr-последовательностью,
или
B) ферментную систему CRISPR, где система кодируется векторной системой, содержащей один или несколько векторов, содержащих:
I. первый регуляторный элемент, функционально связанный с полинуклеотидной последовательностью химерной РНК (chiRNA) системы CRISPR-CAS, где полинуклеотидная последовательность содержит
(a) одну или несколько направляющих последовательностей, способных гибридизироваться с одной или несколькими целевыми последовательностями в эукариотической клетке,
(b) парную tracr-последовательность и
(c) одну или несколько tracr-последовательностей, и
II. второй регуляторный элемент, функционально связанный с кодирующей фермент последовательностью, кодирующей фермент CRISPR, содержащий по меньшей мере одну или несколько последовательностей ядерной локализации,
где (а), (b) и (с) расположены в 5'-3' ориентации,
где компоненты I и II находятся в одном и том же или в разных векторах системы,
где при транскрипции парная tracr-последовательность гибридизируется с tracr-
последовательностью, а направляющая последовательность управляет специфичным к последовательности связыванием комплекса CRISPR с целевой последовательностью,
где комплекс CRISPR содержит фермент CRISPR, образующий комплекс с (1) направляющей последовательностью, которая гибридизируется с целевой последовательностью, и (2) парной tracr-последовательностью, которая гибридизируется с tracr-последовательностью,
или
C) мультиплексную ферментную систему CRISPR, где система кодируется векторной системой, содержащей один или несколько векторов, содержащих
I. первый регуляторный элемент, функционально связанный с полинуклеотидной последовательностью химерной РНК (chiRNA) системы CRISPR-CAS, где полинуклеотидная последовательность содержит
(a) одну или несколько направляющих последовательностей, способных гибридизироваться с одной или несколькими целевыми последовательностями в эукариотической клетке,
(b) парную tracr-последовательность и
(c) одну или несколько tracr-последовательностей, и
II. второй регуляторный элемент, функционально связанный с кодирующей фермент последовательностью, кодирующей фермент CRISPR, содержащий по меньшей мере одну или несколько последовательностей ядерной локализации,
где (а), (b) и (с) расположены в 5'-3' ориентации,
где компоненты I и II находятся в одном и том же или в разных векторах системы,
где при транскрипции парная tracr-последовательность гибридизируется с tracr-последовательностью, а направляющая последовательность управляет специфичным к последовательности связыванием комплекса CRISPR с целевой последовательностью,
где комплекс CRISPR содержит фермент CRISPR, образующий комплекс с (1) направляющей последовательностью, которая гибридизируется с целевой последовательностью, и (2) парной tracr-последовательностью, которая гибридизируется с tracr-последовательностью,
где в мультиплексной системе используется множество полинуклеотидных последовательностей chiRNA,
или
D) мультиплексную ферментную систему CRISPR, где система кодируется векторной системой, содержащей один или несколько векторов, содержащих
I. первый регуляторный элемент, функционально связанный с
(a) одной или несколькими направляющими последовательностями, способными гибридизироваться с целевой последовательностью в клетке, и
(b) по меньшей мере одной или несколькими парными tracr-последовательностями,
II. второй регуляторный элемент, функционально связанный с кодирующей фермент последовательностью, кодирующей фермент CRISPR, и
III. третий регуляторный элемент, функционально связанный с tracr-последовательностью,
где компоненты I, II и III находятся в одном и том же или в разных векторах системы,
где при транскрипции парная tracr-последовательность гибридизируется с tracr-последовательностью, а направляющая последовательность управляет специфичным к последовательности связыванием комплекса CRISPR с целевой последовательностью,
где комплекс CRISPR содержит фермент CRISPR, образующий комплекс с (1) направляющей последовательностью, которая гибридизируется с целевой последовательностью, и (2) парной tracr-последовательностью, которая гибридизируется с tracr-последовательностью, и
где в мультиплексной системе используется множество направляющих последовательностей и одна tracr-последовательность;
и
где в полинуклеотидной последовательности из А) или в системе из В), С) или D) одна или несколько из направляющих, tracr- и парных tracr-последовательностей модифицируются с повышением стабильности.
2. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает сконструированную вторичную структуру.
3. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает уменьшение участка гибридизации между парной tracr-последовательностью и tracr-последовательностью.
4. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает слияние парной tracr-последовательности и tracr-последовательности посредством искусственной петли.
5. chiRNA системы CRISPR-Cas или ферментная система CRISPR п. 1, где модификация включает tracr-последовательность длиной от 40 до 120 п.о.
6. chiRNA системы CRISPR-Cas или ферментная система CRISPR п. 1, где tracr-последовательность составляет от 40 п.о. до полной длины tracr.
7. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где tracr-последовательность включает по меньшей мере нуклеотиды 1-67 соответствующей tracRNA дикого типа.
8. chiRNA системы CRISPR-Cas или ферментная система CRISPR п. 1, где tracr-последовательность включает по меньшей мере нуклеотиды 1-85 соответствующей tracRNA дикого типа.
9. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где tracr-последовательность содержит нуклеотиды, соответствующие нуклеотидам 1-67 tracRNA Cas9 S. pyogenes дикого типа.
10. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где tracr-последовательность содержит нуклеотиды, соответствующие нуклеотидам 1-85 tracRNA Cas9 S. pyogenes дикого типа.
11. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 9, где tracr-последовательность состоит, по сути, из нуклеотидов, соответствующих нуклеотидам 1-67 tracRNA Cas9 S. pyogenes дикого типа.
12. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 10, где tracr-последовательность состоит, по сути, из нуклеотидов, соответствующих нуклеотидам 1-85 tracRNA Cas9 S. pyogenes дикого типа.
13. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает оптимизацию последовательности.
14. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 13, где модификация включает уменьшение полиТ-последовательностей в tracr- и/или парной tracr-последовательности.
15. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 14, где один или несколько Т, присутствующие в полиТ-последовательности соответствующей последовательности дикого типа, были заменены на отличный от Т нуклеотид.
16. chiRNA системы CRISPR-Cas или ферментная система CRISPR по пп. 13, 14 или 15, где модифицированная последовательность не содержит какую-либо полиТ-последовательность, имеющую более 4 смежных Т.
17. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает добавление терминаторной полиТ-последовательности.
18. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 17, где модификация включает добавление терминаторной полиТ-последовательности в tracr-и/или парные tracr-последовательности.
19. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 17 или п. 18, где модификация включает добавление терминаторной полиТ-последовательности в направляющую последовательность.
20. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает изменение петель и/или "шпилек".
21. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 20, где модификация включает обеспечение минимум двух "шпилек" в направляющей последовательности.
22. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 20 или 21, где модификация включает обеспечение "шпильки", образованной при помощи комплементации между tracr- и парной tracr-последовательностью.
23. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 20 или 21, где модификация включает обеспечение одной или нескольких дополнительных "шпилек" на 3'-конце последовательности tracrRNA.
24. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 20 или 21, где модификация включает обеспечение одной или нескольких дополнительных "шпилек", добавленных на 3' направляющей последовательности.
25. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает удлинение 5'-конца направляющей последовательности.
26. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 25, где модификация включает обеспечение одной или нескольких "шпилек" на 5'-конце направляющей последовательности.
27. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 25 или п. 26, где модификация включает введение последовательности (5'-AGGACGAAGTCCTAA) на 5'-конце направляющей последовательности.
28. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает обеспечение образования перекрестных связей или обеспечение одного или нескольких модифицированных нуклеотидов в полинуклеотидной последовательности.
29. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 28, где модифицированные нуклеотиды предусматриваются в любой или во всех из tracr-, парных tracr- и/или направляющих последовательностей, и/или в кодирующей фермент последовательности, и/или в векторных последовательностях.
30. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 28 или 29, где обеспечение модифицированных нуклеотидов предусматривает включение по меньшей мере одного не встречающегося в природе нуклеотида или модифицированного нуклеотида, или их аналогов.
31. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 30, где модифицированные нуклеотиды модифицируются по фрагменту рибозы, фосфата и/или основания.
32. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 30, где модифицированный нуклеотид выбран из группы, состоящей из 2'-O-метил-аналогов, 2'-дезокси-аналогов или 2'-фтор-аналогов.
33. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 30, где модифицированный нуклеотид выбран из группы, состоящей из 2-аминопурина, 5-бромуридина, псевдоуридина, инозина, 7-метилгуанозина.
34. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает две "шпильки".
35. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает три "шпильки".
36. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает самое большее пять "шпилек".
37. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент CRISPR является ферментом системы CRISPR II типа.
38. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент CRISPR является ферментом Cas9.
39. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент CRISPR состоит менее чем из одной тысячи аминокислот.
40. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент CRISPR состоит менее чем из четырех тысяч аминокислот.
41. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент Cas9 представляет собой StCas9 или StlCas9.
42. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент Cas9 является ферментом Cas9 из организма, выбранного из группы, состоящей из рода Streptococcus, Campylobacter, Nitratifractor, Staphylococcus, Parvibaculum, Roseburia, Neisseria, Gluconacetobacter, Azospirillum, Sphaerochaeta, Lactobacillus, Eubacterium или Corynebacter.
43. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где фермент CRISPR является нуклеазой, управляющей расщеплением обеих нитей в определенной точке целевой последовательности.
44. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где первый регуляторный элемент является промотором полимеразы III.
45. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где второй регуляторный элемент является промотором полимеразы II.
46. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где направляющая последовательность содержит по меньшей мере пятнадцать нуклеотидов.
47. chiRNA системы CRISPR-Cas или ферментная система CRISPR по п. 1, где модификация включает оптимизированную tracr-последовательность и/или оптимизированную направляющую последовательность РНК, и/или совместно свернутую структуру tracr-последовательности и/или парной(ых) tracr-последовательности(ей), и/или стабилизирующие вторичные структуры tracr-последовательности, и/или tracr-последовательности с уменьшенным участком спаривания оснований, и/или tracr-последовательность, слитую с элементами РНК; и/или в мультиплексной системе находятся две РНК, содержащие индикатор и содержащие множество гидов, или одна РНК, содержащая множество химерных элементов.
48. chiRNA системы CRISPR-Cas или ферментная система CRISPR по любому из пп. 1-15, 17-18, 20-21, 25-26, 28-29 и 31-47, где фермент CRISPR кодон-оптимизирован для экспрессии в эукариотической клетке.
49. Композиция по п. 1, где композиция содержит полинуклеотидную последовательность химерной РНК (chiRNA) системы CRISPR-CAS.
50. Композиция по п. 49, где композиция дополнительно содержит полинуклеотидную последовательность, кодирующую фермент CRISPR, содержащий по меньшей мере одну или несколько последовательностей ядерной локализации.
51. Ферментная система CRISPR по п. 1.
52. Мультиплексная ферментная система CRISPR по п. 1.
53. Продукт транскрипции или трансляции композиции по п. 49 или 50, ферментная система CRISPR по п. 51 или мультиплексная ферментная система CRISPR по п. 52.
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