RU2016145964A - Композиции и способы для лечения гемоглобинопатий - Google Patents

Композиции и способы для лечения гемоглобинопатий Download PDF

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RU2016145964A
RU2016145964A RU2016145964A RU2016145964A RU2016145964A RU 2016145964 A RU2016145964 A RU 2016145964A RU 2016145964 A RU2016145964 A RU 2016145964A RU 2016145964 A RU2016145964 A RU 2016145964A RU 2016145964 A RU2016145964 A RU 2016145964A
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Майкл МИЛСАМ
Дэвид А. ВИЛЛИАМС
Ричард ГРЕГОРИ
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Чилдрен'С Медикал Сентр Корпорэйшн
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Claims (28)

1. Синтетическая микроРНК к BCL11 А, содержащая;
a) первый участок BCL11A, участок петли и
b) второй участок BCL11A, расположенные последовательно в направлении от 5' к 3',
где участок петли расположен между первым и вторым участками BCL11A и прямо связан с ними и
где второй участок BCL11A комплементарен первому участку BCL11A так, что основания первого и второго участков BCL11A спарены с формированием петли шпильки с участком петли, формирующим область петли сформированной таким образом петли шпильки.
2. Синтетическая микроРНК к BCL11A по п. 1, где длина первого и второго участков BCL11A составляет приблизительно от 18 до 25 нуклеотидов.
3. Синтетическая микроРНК к BCL11A по пп. 1 или 2, где
(a) первый участок BCL11A содержит последовательность, получаемую из последовательности мРНК BCL11A;
(b) первый участок BCL11A комплементарен второму участку BCL11A;
(c) первый участок BCL11A на 5'-конце начинается с -GCGC-, и второй участок BCL11A на 3'-конце заканчивается -GCGC-; или
(d) первый участок BCL11A содержит нуклеотидную последовательность, приведенную в любой из SEQ ID NO: 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 и 67.
4. Синтетическая микроРНК к BCL11A по любому из пп. 1-3, где участок петли получают из микроРНК.
5. Синтетическая микроРНК к BCL11A по любому из пп. 1-4, где микроРНК содержит нуклеотидную последовательность, приведенную в любой из SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 и 44.
6. Способ увеличения уровней фетального гемоглобина, экспрессируемого клеткой, включающий экспрессию по меньшей мере одной синтетической микроРНК к BCL11A по любому из пп. 1-5 в клетке, где клетка представляет собой эмбриональную стволовую клетку, соматическую стволовую клетку, клетку-предшественника, клетку костного мозга, гемопоэтическую стволовую клетку или гемопоэтическую клетку-предшественника.
7. Выделенная молекула нуклеиновой кислоты, содержащая нуклеотидную последовательность, приведенную в любой из SEQ ID NO: 30, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 15, 16, 17, 18, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 и 44.
8. Вектор, содержащий выделенную молекулу нуклеиновой кислоты по п. 7.
9. Клетка-хозяин, содержащая вектор по п. 8.
10. Клетка по п. 9, где
(a) клетка представляет собой эмбриональную стволовую клетку, соматическую стволовую клетку, клетку-предшественника, клетку костного мозга, гемопоэтическую стволовую клетку или гемопоэтическую клетку-предшественника; или
(b) клетка представляет собой эритроцит.
11. Вирус, содержащий выделенную молекулу нуклеиновой кислоты по п. 7.
12. Вирус по п. 11, где вирус представляет собой
(a) лентивирус или
(b) лентивирус, выбранный из группы, состоящей из: вируса иммунодефицита человека типа 1 (ВИЧ-1), вируса иммунодефицита человека типа 2 (ВИЧ-2), вируса артрита-энцефалита коз и овец (CAEV), вируса инфекционной анемии лошадей (EIAV), вируса иммунодефицита кошек (FIV), вируса иммунодефицита крупного рогатого скота (BIV) и вируса иммунодефицита обезьян (SIV).
13. Композиция, содержащая синтетическую микроРНК к BCL11A по любому из пп. 1-5; выделенную молекулу нуклеиновой кислоты по п. 7; вектор по п. 8; клетку-хозяина по п. 9 или 10; или вирус по п. 11 или 12.
14. Композиция по п. 13, дополнительно содержащая фармацевтически приемлемый носитель или разбавитель.
15. Композиция по п. 13 или 14 для применения в производстве лекарственного средства для лечения или снижение риска развития гемоглобинопатии у индивидуума.
16. Способ лечения или снижения риска развития гемоглобинопатии у индивидуума, где способ включает: введение индивидууму терапевтически эффективного количества синтетической микроРНК к BCL11A по любому из пп. 1-5; выделенной молекулы нуклеиновой кислоты по п. 7; вектор по 8; клетка-хозяин по п. 9 или 10; или вирус по п. 11 или 12, таким образом, обеспечивая лечение или снижение риска развития гемоглобинопатии у индивидуума.
RU2016145964A 2014-04-25 2015-04-24 Композиции и способы для лечения гемоглобинопатий RU2707540C2 (ru)

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US201461984247P 2014-04-25 2014-04-25
US61/984,247 2014-04-25
US201462066783P 2014-10-21 2014-10-21
US62/066,783 2014-10-21
PCT/US2015/027527 WO2015164750A2 (en) 2014-04-25 2015-04-24 Compositions and methods to treating hemoglobinopathies

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