RU2016136977A - Композиции для инактивации репликации вируса и способы их получения и применения - Google Patents
Композиции для инактивации репликации вируса и способы их получения и применения Download PDFInfo
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Claims (40)
1. Конструкция, содержащая первый промотор, функционально связанный с первым полинуклеотидом, кодирующим первую одиночную направляющую РНК, и второй промотор, функционально связанный с вторым полинуклеотидом, кодирующим полипептид Cas9, где первая одиночная направляющая РНК содержит первую часть, комплементарную цепи последовательности-мишени вируса и вторую часть, способную взаимодействовать с полипептидом Cas9.
2. Конструкция по п.1, где вирус классифицирован по семейству, выбранному из группы, состоящей из Hepadnaviridae, herpesviridae, papillomaviridae и retroviridae.
3. Конструкция по п.1, где вирус выбран из группы, состоящей из вируса простого герпеса типа 1 (HSV-1), вируса простого герпеса типа 2 (HSV-2), вируса Эпштейна-Барр (EBV), цитомегаловируса человека (hCMV), вируса ветряной оспы (VZV), ассоциированного с саркомой Капоши вируса герпеса (KSHV), вируса гепатита B (HBV), вируса папилломы человека (HPV) и вируса иммунодефицита человека (ВИЧ-1).
4. Конструкция по п.3, где последовательность-мишень выбрана из группы, состоящей из ICP0 HSV, ICP4 HSV, ассоциированного с вирусной латентностью транскрипта HSV, FR (семейство повторов) EBV, DR (прямая симметрия) EBV, ядерного антигена EBV (EBNA1), промотора Qp EBV, гена латентного мембранного белка-1 (LMP-1) EBV, обратной транскриптазы HBV, поверхностного антигена HBV, сердцевины HBV, гена E6 HPV и гена E7 HPV, Tat ВИЧ-1 и TAR ВИЧ-1 или прилегающих промоторных последовательностей.
5. Конструкция по п.4, где первая часть одиночной направляющей РНК выбрана из SEQ ID NO: 1-27, 30-35 и 63.
6. Конструкция по любому из пп.1-5, где первый промотор представляет собой промотор для РНК-полимеразы III, выбранный из группы, состоящей из промотора U6, тРНК Gln, тРНК Pro, тРНК Gly, тРНК Asn, тРНК Cys, тРНК Glu, тРНК гамма-вируса герпеса-68 мыши (MHV68) или любой тРНК млекопитающих.
7. Конструкция по п.6, где промотор содержит по меньшей мере одну из SEQ ID NO: 41-50.
8. Конструкция по любому из пп.1-7, где полипептид Cas9 выбран из полипептидов Cas9 из S. pyogenes, S. aureus, или никаз Cas9 и их производных.
9. Конструкция по п.8, где полипептид Cas9 содержит SEQ ID NO: 57 или кодирован полинуклеотидом, содержащим SEQ ID NO: 55.
10. Конструкция по п.9, дополнительно содержащая по меньшей мере один из сигнала ядерной локализации, интрона или участка добавления поли(A).
11. Конструкция по любому из пп.1-10, где второй промотор представляет собой зависимый от РНК-полимеразы II промотор/энхансер, выбранный из группы, состоящей из промотора/энхансера EFS, немедленного раннего hCMV или mCMV, CBA, h-синапсина, TK HSV, раннего SV40 и LSP.
12. Конструкция по любому из пп.1-11, дополнительно содержащая первый инвертированный концевой повтор и второй инвертированный концевой повтор, где инвертированные концевые повторы фланкируют конструкцию для упаковки в вектор на основе аденоассоциированного вируса (AAV).
13. Конструкция по любому из пп.1-12, дополнительно содержащая третий промотор, функционально связанный с третьим полинуклеотидом, кодирующим вторую одиночную направляющую РНК, содержащую первую часть, комплементарную цепи второй последовательности-мишени вируса, где третий промотор представляет собой зависимый от РНК-полимеразы III промотор.
14. Конструкция по п.13, где первая последовательность-мишень и вторая последовательность-мишень локализованы в пределах 30 пар оснований друг от друга на противоположных цепях вируса.
15. Рекомбинантный вектор, содержащий конструкцию по любому из пп.1-14.
16. Рекомбинантный вектор по п.15, где вектор представляет собой вирусный вектор, и вирусный вектор выбран из группы, состоящей из ретровируса, лентивируса, аденовируса или аденоассоциированного вируса.
17. Фармацевтическая композиция, содержащая рекомбинантный вектор по любому из пп.15-16 и фармацевтический носитель.
18. Способ ингибирования репликации вируса или экспрессии последовательности-мишени в клетке, инфицированной вирусом, включающий приведение клетки в контакт с рекомбинантным вектором по любому из пп.15-16 или с конструкцией по любому из пп.1-14 в количестве, эффективном, чтобы обеспечивать доставку рекомбинантного вектора или конструкции в клетку и продукцию одиночной направляющей РНК и полипептида Cas9.
19. Способ по п.18, где одиночная направляющая РНК и полипептид Cas9 расщепляют последовательность-мишень.
20. Способ по п.18 или 19, где две или более одиночных направляющих РНК присутствуют в рекомбинантном векторе или конструкции, и расщепляется более одной последовательности-мишени.
21. Способ по любому из пп.18-20, где экспрессия продукта гена, кодированного последовательностью-мишенью, уменьшается после контакта с рекомбинантным вектором или конструкцией и продукцией одиночной направляющей РНК и полипептида Cas9.
22. Способ по любому из пп.18-21, где последовательность-мишень изменяется после контакта с рекомбинантным вектором или конструкцией.
23. Способ по любому из пп.18-22, где вирус является неспособным реплицироваться в клетке или выводится из клетки после контакта с рекомбинантным вектором или конструкцией.
24. Способ по любому из пп.18-23, где контакт происходит in vitro.
25. Способ лечения вирусной инфекции у пациента, включающий введение эффективного количества рекомбинантного вектора по любому из пп.15-16 или фармацевтической композиции по п.17 пациенту для лечения вирусной инфекции.
26. Способ по п.25, где введение уменьшает геномную нагрузку или количество вирусных эписом вируса у пациента, уменьшает репликацию вируса у пациента или уменьшает экспрессию продукта гена, кодированного последовательностью-мишенью, у пациента.
27. Рекомбинантный полипептид Cas9 Sau из SEQ ID NO: 57.
28. Рекомбинантная конструкция Cas9 Sau, содержащая промотор, функционально связанный с полинуклеотидом, кодирующим рекомбинантный полипептид Cas9 Sau, где полинуклеотид содержит SEQ ID NO: 55.
29. Рекомбинантная конструкция Cas9 Sau по п.28, дополнительно содержащая участок добавления поли(A) и сигнал ядерной локализации.
30. Рекомбинантная конструкция Cas9 Sau по п.28 или 29, дополнительно содержащая интрон.
31. Рекомбинантная конструкция Cas9 Sau по любому из пп.28-30, где промотор представляет собой зависимый от РНК-полимеразы II промотор/энхансер, выбранный из группы, состоящей из промотора/энхансера EFS, hCMV, mCMV, CBA, h-синапсина, TK HSV, раннего SV40 и LSP.
32. Рекомбинантная конструкция Cas9 Sau по любому из пп.28-31, имеющая SEQ ID NO: 58.
33. Рекомбинантная конструкция для экспрессии одиночной направляющей РНК, содержащая первый полинуклеотид, кодирующий тРНК млекопитающих или вирусов, функционально связанный с вторым полинуклеотидом, кодирующим по меньшей мере вторую часть одиночной направляющей РНК, способную взаимодействовать с полипептидом Cas9.
34. Конструкция по п.33, где первый полинуклеотид выбран из SEQ ID NO: 41-50.
35. Конструкция по п.33 или 34, где второй полинуклеотид дополнительно кодирует первую часть одиночной направляющей РНК, комплементарную последовательности-мишени, на 5’- от второй части, способной взаимодействовать с полипептидом Cas9.
36. Конструкция по любому из пп.33-35, где второй полинуклеотид дополнительно кодирует первую часть одиночной направляющей РНК, обладающую одним или несколькими участками узнавания для рестрикционных эндонуклеаз.
37. Конструкция по любому из пп.33-36, дополнительно содержащая промотор, функционально связанный с третьим полинуклеотидом, кодирующим полипептид Cas9.
38. Набор, содержащий рекомбинантную конструкцию Cas9 Sau по любому из пп.28-32.
39. Набор, содержащий рекомбинантную конструкцию по любому из пп.33-37.
40. Набор по п.39, дополнительно содержащий рекомбинантную конструкцию Cas9 Sau по любому из пп.28-32.
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