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RU2012144738A - САМОДОСТАВЛЯЮЩИЕ PHKi СОЕДИНЕНИЯ УМЕНЬШЕННОГО РАЗМЕРА - Google Patents

САМОДОСТАВЛЯЮЩИЕ PHKi СОЕДИНЕНИЯ УМЕНЬШЕННОГО РАЗМЕРА Download PDF

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RU2012144738A
RU2012144738A RU2012144738/04A RU2012144738A RU2012144738A RU 2012144738 A RU2012144738 A RU 2012144738A RU 2012144738/04 A RU2012144738/04 A RU 2012144738/04A RU 2012144738 A RU2012144738 A RU 2012144738A RU 2012144738 A RU2012144738 A RU 2012144738A
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rxphk
modifications
methyl
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nucleotides
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Анастасия ХОВОРОВА
Уильям САЛОМОН
Джоан КАМЕНС
Дмитрий САМАРСКИЙ
Тод М. ВУЛЬФ
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Abstract

1. sd-rxPHK, в которой, по меньшей мере, 40% нуклеотидов модифицированы и в которой, по меньшей мере, два Us и/или Cs включают гидрофобную модификацию, выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.2. sd-rxPHK по п.1, отличающаяся тем, что, по меньшей мере, 60% нуклеотидов модифицированы.3. sd-rxPHK по п.1, отличающаяся тем, что модификации включают, по меньшей мере, одну 2′F или 2′O метильную модификацию.4. sd-rxPHK по п.1, отличающаяся тем, что множество Us и/или Cs включают гидрофобную модификацию, необязательно выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.5. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK присоединена к линкеру.6. sd-rxPHK по п.5, отличающаяся тем, что линкер является протонируемым.7. sd-rxPHK по п.6, отличающаяся тем, что sd-rxPHK присоединена к множеству линкеров.8. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK связана на 3′ конце с липофильной группой.9. sd-rxPHK по п.8, отличающаяся тем, что sd-rxPHK связана с холестерином.10. sd-rxPHK по п.8, отличающаяся тем, что sd-rxPHK присоединена к витамину А или витамину Е.11. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что ведущая нить содержит одноцепочечную область, содержащую, по меньшей мере, 5 фосфоротиоатных модификаций.12. sd-rxPHK по п.11, отличающаяся тем, что sd-rxPHK содержит, по меньшей мере, две одноцепочечные области.13. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK составлена в композицию для внутривенного введения.14. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK составлена в композицию для подкожного введени�

Claims (51)

1. sd-rxPHK, в которой, по меньшей мере, 40% нуклеотидов модифицированы и в которой, по меньшей мере, два Us и/или Cs включают гидрофобную модификацию, выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
2. sd-rxPHK по п.1, отличающаяся тем, что, по меньшей мере, 60% нуклеотидов модифицированы.
3. sd-rxPHK по п.1, отличающаяся тем, что модификации включают, по меньшей мере, одну 2′F или 2′O метильную модификацию.
4. sd-rxPHK по п.1, отличающаяся тем, что множество Us и/или Cs включают гидрофобную модификацию, необязательно выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
5. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK присоединена к линкеру.
6. sd-rxPHK по п.5, отличающаяся тем, что линкер является протонируемым.
7. sd-rxPHK по п.6, отличающаяся тем, что sd-rxPHK присоединена к множеству линкеров.
8. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK связана на 3′ конце с липофильной группой.
9. sd-rxPHK по п.8, отличающаяся тем, что sd-rxPHK связана с холестерином.
10. sd-rxPHK по п.8, отличающаяся тем, что sd-rxPHK присоединена к витамину А или витамину Е.
11. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что ведущая нить содержит одноцепочечную область, содержащую, по меньшей мере, 5 фосфоротиоатных модификаций.
12. sd-rxPHK по п.11, отличающаяся тем, что sd-rxPHK содержит, по меньшей мере, две одноцепочечные области.
13. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK составлена в композицию для внутривенного введения.
14. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK составлена в композицию для подкожного введения.
15. sd-rxPHK по любому из пп.1-4, отличающаяся тем, что sd-rxPHK составлена в композицию для интратекального введения.
16. sd-rxPHK по любому из пп.1-4, при этом период полураспада sd-rxPHK в сыворотке составляет более, чем 12 часов.
17. Композиция, содержащая sd-rxPHK по любому из пп.1-16.
18. Композиция по п.17, отличающаяся тем, что композиция содержит две или более разных sd-rxPHK.
19. Двухцепочечная РНК (dsPHK), в которой, по меньшей мере, 40% нуклеотидов модифицированы, и в которой, по меньшей мере, два Us и/или Cs включают гидрофобную модификацию, выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
20. dsPHK по п.19, отличающаяся тем, что, по меньшей мере, 60% нуклеотидов модифицированы.
21. dsPHK по п.19, отличающаяся тем, что модификации включают, по меньшей мере, одну 2′F или 2′О метильную модификацию.
22. dsPHK по любому из пп.19-21, отличающаяся тем, что множество Us и/или Cs включают гидрофобную модификацию, необязательно выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
23. Одноцепочечный RISC входящий полинуклеотид, в котором, по меньшей мере, 40% нуклеотидов модифицированы, и в котором, по меньшей мере, два Us и/или Cs включают гидрофобную модификацию, выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
24. Одноцепочечный RISC входящий полинуклеотид по п.23, отличающийся тем, что, по меньшей мере, 60% нуклеотидов модифицированы.
25. Одноцепочечный RISC входящий полинуклеотид по п.23, отличающийся тем, что модификации включают, по меньшей мере, одну 2′F или 2′O метильную модификацию.
26. Одноцепочечный RISC входящий полинуклеотид по любому из пп.23-25, отличающийся тем, что множество Us и/или Cs включают гидрофобную модификацию, необязательно выбранную из группы, состоящей из метильной, октильной, тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
27. Одноцепочечный RISC входящий полинуклеотид по любому из пп.23-25, отличающийся тем, что выделенный одноцепочечный RISC входящий полинуклеотид является miPHK ингибитором.
28. Способ доставки нуклеиновой кислоты в отдаленную ткань-мишень у субъекта, который нуждается в этом, включающий стадию, на которой:
системно вводят субъекту sd-rxPHK в эффективном количестве для способствования РНК интерференции при помощи sd-rxPHK в упомянутой отдаленной ткани-мишени.
29. Способ по п.28, отличающийся тем, что, по меньшей мере, 40% нуклеотидов в антисмысловой нити sd-rxPHK модифицированы.
30. Способ по п.29, отличающийся тем, что, по меньшей мере, 60% нуклеотидов в антисмысловой нити sd-rxPHK модифицированы.
31. Способ по п.29 или 30, отличающийся тем, что модификации включают, по меньшей мере, одну 2′F или 2′O метильную модификацию.
32. Способ по любому из пп.28-30, отличающийся тем, что, по меньшей мере, один U или С включает гидрофобную модификацию.
33. Способ по п.32, отличающийся тем, что множество Us и/или Cs включают гидрофобную модификацию.
34. Способ по п.33, отличающийся тем, что гидрофобную модификацию выбирают и группы, состоящей из октильной. тиофеновой, октин-1-ильной, этинильной, пиридиламидной, изобутильной и фенильной модификации.
35. Способ по любому из пп.28-30, отличающийся тем, что sd-rxPHK присоединена к линкеру.
36. Способ по п.35, отличающийся тем, что линкер является протонируемым.
37. Способ по п.36, отличающийся тем, что sd-rxPHK присоединена ко множеству линкеров.
38. Способ по любому из пп.28-30, отличающийся тем, что sd-rxPHK связана на 3′ конце с липофильной группой.
39. Способ по п.38, отличающийся тем, что sd-rxPHK связана с холестерином.
40. Способ по п.38, отличающийся тем, что sd-rxPHK присоединена к витамину А или витамину Е.
41. Способ по любому из пп.28-30, отличающийся тем, что ведущая нить sd-rxPHK содержит одноцепочечную область, содержащую, по меньшей мере, 5 фосфоротиоатных модификаций.
42. Способ по п.41, отличающийся тем, что ведущая нить sd-rxPHK содержит, по меньшей мере, две одноцепочечных области.
43. Способ по любому из пп.28-30, отличающийся тем, что sd-rxPHK доставляется в печень, сердце, легкие или жир.
44. Способ по любому из пп.28-30, отличающийся тем, что sd-rxPHK доставляется в опухоль.
45. Способ по любому из пп.28-30, отличающийся тем, что sd-rxPHK вводят подкожно.
46. Способ, включающий стадию, на которой:
вводят субъекту, имеющему опухоль, sd-rxPHK в эффективном количестве, для способствования РНК интерференции, при помощи sd-rxPHK в опухоли.
47. Способ по п.46, отличающийся тем, что sd-rxPHK вводят в опухоль посредством внутривенного введения.
48. Способ по п.46, отличающийся тем, что sd-rxPHK вводят в опухоль посредством прямой инъекции в опухоль.
49. Способ по любому из пп.46-48, отличающийся тем, что sd-rxPHK направлена против гена, кодирующего белок, выбранный из группы, состоящей из: VEGF/VEGFR, HER2, PDGF/PDGFR, HDAC, MET, c-kit, CDK, FLT-1, IGF/IGFR, FGF/FGFR, Ras/Raf, Abl, Bcl-2, Src, mTOR, PKC, МАРК, BIRC5, FAS, HIF1A, CDH16, MYC, HRAS и CTNNB1 или их комбинации.
50. Способ, включающий стадию, на которой:
вводят sd-rxPHK в центральную нервную систему субъекта, который нуждается в этом.
51. Способ по п.50, отличающийся тем, что sd-rxPHK вводят путем интратекальной доставки.
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