RU2013148024A - Композиции и способы ингибирования экспрессии гена tmprss6 - Google Patents

Композиции и способы ингибирования экспрессии гена tmprss6 Download PDF

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RU2013148024A
RU2013148024A RU2013148024/10A RU2013148024A RU2013148024A RU 2013148024 A RU2013148024 A RU 2013148024A RU 2013148024/10 A RU2013148024/10 A RU 2013148024/10A RU 2013148024 A RU2013148024 A RU 2013148024A RU 2013148024 A RU2013148024 A RU 2013148024A
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dsrna
seq
nucleotide
nucleotides
dsrna according
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Дэвид Бумкрот
Брайан БЕТТЕНКОРТ
Иванка Тудьярска
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Элнилэм Фармасьютикалз, Инк.
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Abstract

1. Двухцепочечная рибонуклеиновая кислота (dsRNA) для ингибирования экспрессии TMPRSS6, где указанная dsRNA включает смысловую цепь и антисмысловую цепь, причем антисмысловая цепь включает область комплементарности транскрипту TMPRSS6, включающую, по меньшей мере, 15 непрерывных нуклеотидов, отличающуюся не более чем на 3 нуклеотида от одной из антисмысловых последовательностей, представленных в таблицах 2, 3 или 4.2. dsRNA по п. 1, где указанная dsRNA включает, по меньшей мере, один модифицированный нуклеотид.3. dsRNA по п. 2, где, по меньшей мере, один из указанных модифицированных нуклеотидов выбран из группы, состоящей из: 2′-O-метил-модифицированного нуклеотида, нуклеотида, включающего 5′-фосфоротиоатную группу, и концевого нуклеотида, связанного с холестериловым производным или с бисдециламидной группой додекановой кислоты.4. dsRNA по п. 2, где указанный модифицированный нуклеотид выбран из группы, состоящей из: 2′-дезокси-2′-фтор-модифицированного нуклеотида, 2′-дезокси-модифицированного нуклеотида, блокированного нуклеотида, абазического нуклеотида, 2′-амино-модифицированного нуклеотида, 2′-алкил-модифицированного нуклеотида, морфолинонуклеотида, фосфорамидата и неприродного основания, включающего нуклеотид.5. dsRNA по п. 1, где область комплементарности состоит, по меньшей мере, из 17 нуклеотидов в длину.6. dsRNA по п. 1, где область комплементарности содержит от 19 до 21 нуклеотида в длину.7. dsRNA по п. 1, где область комплементарности содержит 19 нуклеотидов в длину.8. dsRNA по п. 1, где каждая цепь содержит не более 30 нуклеотидов в длину.9. dsRNA по п. 1, где, по меньшей мере, одна цепь включает 3′-липкий конец, по меньшей мере, из 1 нуклеотида.10. dsRNA по п. 1, г�

Claims (31)

1. Двухцепочечная рибонуклеиновая кислота (dsRNA) для ингибирования экспрессии TMPRSS6, где указанная dsRNA включает смысловую цепь и антисмысловую цепь, причем антисмысловая цепь включает область комплементарности транскрипту TMPRSS6, включающую, по меньшей мере, 15 непрерывных нуклеотидов, отличающуюся не более чем на 3 нуклеотида от одной из антисмысловых последовательностей, представленных в таблицах 2, 3 или 4.
2. dsRNA по п. 1, где указанная dsRNA включает, по меньшей мере, один модифицированный нуклеотид.
3. dsRNA по п. 2, где, по меньшей мере, один из указанных модифицированных нуклеотидов выбран из группы, состоящей из: 2′-O-метил-модифицированного нуклеотида, нуклеотида, включающего 5′-фосфоротиоатную группу, и концевого нуклеотида, связанного с холестериловым производным или с бисдециламидной группой додекановой кислоты.
4. dsRNA по п. 2, где указанный модифицированный нуклеотид выбран из группы, состоящей из: 2′-дезокси-2′-фтор-модифицированного нуклеотида, 2′-дезокси-модифицированного нуклеотида, блокированного нуклеотида, абазического нуклеотида, 2′-амино-модифицированного нуклеотида, 2′-алкил-модифицированного нуклеотида, морфолинонуклеотида, фосфорамидата и неприродного основания, включающего нуклеотид.
5. dsRNA по п. 1, где область комплементарности состоит, по меньшей мере, из 17 нуклеотидов в длину.
6. dsRNA по п. 1, где область комплементарности содержит от 19 до 21 нуклеотида в длину.
7. dsRNA по п. 1, где область комплементарности содержит 19 нуклеотидов в длину.
8. dsRNA по п. 1, где каждая цепь содержит не более 30 нуклеотидов в длину.
9. dsRNA по п. 1, где, по меньшей мере, одна цепь включает 3′-липкий конец, по меньшей мере, из 1 нуклеотида.
10. dsRNA по п. 1, где, по меньшей мере, одна цепь включает 3′-липкий конец, по меньшей мере, из 2 нуклеотидов.
11. dsRNA по п. 1, дополнительно включающая лиганд.
12. dsRNA по п. 11, где лиганд конъюгирован с 3′-концом смысловой цепи dsRNA.
13. dsRNA по п. 1, где область комплементарности состоит из одной из антисмысловых последовательностей таблиц 2, 3 или 4.
14. dsRNA по п. 1, где dsRNA включает смысловую цепь, состоящую из последовательности смысловой цепи, выбранной из таблиц 2, 3 или 4, и антисмысловую цепь, состоящую из последовательности антисмысловой цепи, выбранной из таблиц 2, 3 или 4.
15. Клетка, содержащая dsRNA по п. 1.
16. Фармацевтическая композиция для ингибирования экспрессии гена TMPRSS6, содержащая dsRNA по п. 1.
17. Фармацевтическая композиция по п. 16, дополнительно содержащая липидный состав.
18. Фармацевтическая композиция по п. 17, где липидный состав представляет собой состав SNALP или XTC.
19. Способ ингибирования экспрессии TMPRSS6 в клетке, причем способ включает:
(a) введение в клетку dsRNA по п. 1; и
(b) поддержание клетки, полученной на стадии (a), в течение времени, достаточного для получения деградации транскрипта мРНК гена TMPRSS6, тем самым ингибируя экспрессию гена TMPRSS6 в клетке.
20. Способ по п. 19, где экспрессия TMPRSS6 ингибируется, по меньшей мере, на 30%.
21. Способ лечения нарушения, опосредуемого экспрессией TMPRSS6, включающий введение человеку, нуждающемуся в таком лечении, терапевтически эффективного количества dsRNA по п. 1 или фармацевтической композиции по пп. 16-18.
22. Способ по п. 21, где человек страдает нарушением, связанным с гемохроматозом.
23. Способ по п. 21, где человек страдает β-талассемией.
24. Способ по п. 21, где человек страдает промежуточной β-талассемией.
25. Способ по п. 23, где введение dsRNA индивидууму вызывает снижение железа в сыворотке индивидуума, по меньшей мере, на 10%.
26. Способ по п. 21, где dsRNA вводят в концентрации 0,01 мг/кг - 5 мг/кг массы тела индивидуума.
27. Вектор, кодирующий, по меньшей мере, одну цепь dsRNA, где указанная dsRNA содержит область комплементарности, по меньшей мере, с одной частью мРНК, кодирующей TMPRSS6, где указанная dsRNA состоит в длину из 30 пар оснований или менее и где указанная dsRNA направлена на указанную мРНК для ее расщепления.
28. Вектор по п. 27, где область комплементарности составляет, по меньшей мере, 15 нуклеотидов в длину.
29. Вектор по п. 27, где область комплементарности состоит из от 19 до 21 нуклеотида в длину.
30. Клетка, включающая вектор по п. 27.
31. dsRNA по п. 1, где dsRNA содержит смысловую цепь, состоящую из последовательности, выбранной из группы, состоящей из SEQ ID NO:111, SEQ ID NO:455, SEQ ID NO:109, SEQ ID NO:524, SEQ ID NO:89, SEQ ID NO:494, SEQ ID NO:445, SEQ ID NO:592, SEQ ID NO:47 и SEQ ID NO:540; и антисмысловую цепь, состоящую из последовательности, выбранной из группы, состоящей из SEQ ID NO:112, SEQ ID NO:456, SEQ ID NO:110, SEQ ID NO:525, SEQ ID NO:90, SEQ ID NO:495, SEQ ID NO:446, SEQ ID NO:593, SEQ ID NO:48 и SEQ ID NO:541.
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