RU2020116369A - Способы лечения инфекции гепатита в - Google Patents

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RU2020116369A
RU2020116369A RU2020116369A RU2020116369A RU2020116369A RU 2020116369 A RU2020116369 A RU 2020116369A RU 2020116369 A RU2020116369 A RU 2020116369A RU 2020116369 A RU2020116369 A RU 2020116369A RU 2020116369 A RU2020116369 A RU 2020116369A
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Мартин КОУЗЕР
Марк АБРАМС
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Дайсерна Фармасьютикалз, Инк
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Claims (52)

1. Олигонуклеотид для снижения экспрессии мРНК поверхностного антигена вируса гепатита В (HBsAg),
содержащий смысловую цепь, образующую дуплексную область с антисмысловой цепью,
где:
смысловая цепь состоит из последовательности, такой как GACAAAAAUCCUCACAAUAAGCAGCCGAAAGGCUGC (SEQ ID NO: 8) и содержащей
2'-фтормодифицированные нуклеотиды в положениях 3, 8-10, 12, 13 и 17,
2'-O-метил-модифицированные нуклеотиды в положениях 1, 2, 4-7, 11, 14-16, 18-26 и 31-36, и
фосфоротиоатную связь между нуклеотидами в положениях 1 и 2,
где каждый из нуклеотидов последовательности -GAAA- смысловой цепи конъюгирован с моновалентным фрагментом GalNac; а
антисмысловая цепь состоит из последовательности, такой как
UUAUUGUGAGGAUUUUUGUCGG (SEQ ID NO: 5.1) и содержащей
2'-фтор-модифицированные нуклеотиды в положениях 2, 3, 5, 7, 8, 10, 12, 14, 16 и 19,
2'-O-метил-модифицированные нуклеотиды в положениях 1, 4, 6, 9, 11, 13, 15, 17, 18 и 20-22, и
фосфоротиоатные связи между нуклеотидами в положениях 1 и 2, между нуклеотидами в положениях 2 и 3, между нуклеотидами в положениях 3 и 4, между нуклеотидами в положениях 20 и 21 и между нуклеотидами в положениях 21 и 22, и
где 4'-углерод сахара 5'-нуклеотида антисмысловой цепи включает метоксифосфонат (MOP).
2. Олигонуклеотид по п. 1, в котором 5'-нуклеотид антисмысловой цепи имеет следующую структуру:
Figure 00000001
.
3. Олигонуклеотид по п. 1 или 2, где последовательность -GAAA- содержит структуру:
Figure 00000002
где:
L представляет собой связь, клик-химическую защёлку или линкер длиной от 1 до 20 включительно последовательных ковалентно связанных атомы в длину, выбранный из группы, состоящей из замещенного и незамещенного алкилена, замещенного и незамещенного алкенилена, замещенного и незамещенного алкинилена, замещенного и незамещенного гетероалкилена, замещенного и незамещенного гетероалкенилена, замещенного и незамещенного гетероалкинилена и комбинации таковых; а также
Х представляет собой О, S или N.
4. Олигонуклеотид по п. 3, где L представляет собой ацетальный линкер.
5. Олигонуклеотид по п. 3 или 4, где Х представляет собой О.
6. Олигонуклеотид по любому из пп. 1-5, где последовательность -GAAA- содержит структуру:
Figure 00000003
7. Олигонуклеотид для снижения экспрессии мРНК поверхностного антигена вируса гепатита В (HBsAg), содержащий смысловую цепь, образующую дуплексную область с антисмысловой цепью, где:
смысловая цепь состоит из последовательности, такой как
GACAAAAAUCCUCACAAUAAGCAGCCGAAAGGCUGC (SEQ ID NO: 8) и содержащей
2'-фтормодифицированные нуклеотиды в положениях 3, 8-10, 12, 13 и 17,
2'-O-метил-модифицированные нуклеотиды в положениях 1, 2, 4-7, 11, 14-16, 18-26 и 31-36, и
одну фосфоротиоатную межнуклеотидную связь между нуклеотидами в положениях 1 и 2,
где каждый из нуклеотидов последовательности -GAAA- смысловой цепи конъюгирован с моновалентным фрагментом GalNac, и где последовательность -GAAA- содержит структуру:
Figure 00000004
; и
антисмысловая цепь состоит из последовательности, такой как
UUAUUGUGAGGAUUUUUGUCGG (SEQ ID NO: 5.1) и содержащей
2'-фтор-модифицированные нуклеотиды в положениях 2, 3, 5, 7, 8, 10, 12, 14, 16 и 19,
2'-O-метил-модифицированные нуклеотиды в положениях 1, 4, 6, 9, 11, 13, 15, 17, 18 и 20-22, и
пять фосфоротиоатных межнуклеотидных связей между нуклеотидами в положениях 1 и 2, между нуклеотидами в положениях 2 и 3, между нуклеотидами в положениях 3 и 4, между нуклеотидами в положениях 20 и 21 и между нуклеотидами в положениях 21 и 22,
где 5'-нуклеотид антисмысловой цепи имеет следующую структуру:
Figure 00000005
 .
8. Композиция, содержащая олигонуклеотид по любому из пп. 1-7.
9. Композиция по п. 8, содержащая противоион.
10. Композиция по п. 8 или 9, содержащая фармацевтически приемлемый носитель.
11. Композиция по любому из пп. 8-10, содержащая эксципиент.
12. Композиция по любому из пп. 8-11, содержащая фосфатно-солевой буферный раствор.
13. Способ снижения in vitro экспрессии поверхностного антигена вируса гепатита B (HBV) (HBsAg) в клетке, включающий доставку в клетку олигонуклеотида по любому из пп. 1-7.
14. Способ по п. 13, где клетка представляет собой гепатоцит.
15. Способ по п. 13 или 14, в котором олигонуклеотид доставляют в форме трансгена, сконструированного для экспрессии олигонуклеотида в клетке.
16. Олигонуклеотид по любому из пп. 1-7 или композиция по любому из пп. 8-12 для применения в способе лечения инфекции HBV у субъекта.
17. Олигонуклеотид или композиция для применения по п. 16, где олигонуклеотид или композицию вводят субъекту подкожно.
18. Олигонуклеотид или композиция для применения по п. 16, где олигонуклеотид или композицию вводится субъекту внутривенно.
19. Композиция для применения по п. 18, содержащая фармацевтически приемлемый носитель, где фармацевтически приемлемый носитель представляет собой растворитель или дисперсионную среду, содержащую воду.
RU2020116369A 2017-10-20 2018-10-19 Способы лечения инфекции гепатита в RU2780021C2 (ru)

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