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RU2017126598A - Рнк-агенты для модуляции гена gst-pi - Google Patents

Рнк-агенты для модуляции гена gst-pi Download PDF

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RU2017126598A
RU2017126598A RU2017126598A RU2017126598A RU2017126598A RU 2017126598 A RU2017126598 A RU 2017126598A RU 2017126598 A RU2017126598 A RU 2017126598A RU 2017126598 A RU2017126598 A RU 2017126598A RU 2017126598 A RU2017126598 A RU 2017126598A
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nucleic acid
cancer
acid molecule
seq
molecule according
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Венбин ИН
Кендзироу МИНОМИ
Йенс ХАРБОРТ
Хирокадзу ТАКАХАСИ
Эрика ТЕРАДА
Дзун ЧЖАН
Мохаммад АХМАДИАН
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Нитто Денко Корпорейшн
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Claims (27)

1. Молекула нуклеиновой кислоты, где:
молекула имеет полинуклеотидную смысловую цепь и полинуклеотидную антисмысловую цепь;
каждая цепь молекулы имеет длину от 15 до 30 нуклеотидов;
непрерывная область от 15 до 30 нуклеотидов антисмысловой цепи комплементарна последовательности мРНК, кодирующей GST-π;
по меньшей мере, часть смысловой цепи комплементарна, по меньшей мере, части антисмысловой цепи, и молекула имеет дуплексную область длиной от 15 до 30 нуклеотидов.
2. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что антисмысловая цепь представляет собой SEQ ID NO: 1341, а смысловая цепь представляет собой SEQ ID NO: 1276 или их химически модифицированные цепи.
3. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что антисмысловая цепь представляет собой SEQ ID NO: 1305, а смысловая цепь представляет собой SEQ ID NO: 1240 или их химически модифицированные цепи.
4. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что непрерывная область антисмысловой цепи длиной от 15 до 30 нуклеотидов, которая комплементарна последовательности мРНК, кодирующей GST-π, расположена в дуплексной области молекулы.
5. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что непрерывную область антисмысловой цепи длиной от 15 до 30 нуклеотидов, которая комплементарна последовательности мРНК, кодирующей GST-π, выбирают из последовательности человеческого GSTP1, где мРНК человеческого GSTP1 представляет собой SEQ ID NO: 1.
6. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что последовательность мРНК, кодирующую GST-π, выбирают из группы, состоящей из 5'UTR-положений 1-249 SEQ ID NO: 1, CDS-положений 250-882 SEQ ID NO: 1, и 3'UTR положений 883-986 SEQ ID NO: 1.
7. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что антисмысловая цепь содержит последовательность, выбранную из любой из SEQ ID NO: 609-1215.
8. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что антисмысловая цепь содержит последовательность, выбранную из любой из SEQ ID NO: 1281-1345.
9. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула состоит из пары антисмысловой и смысловой цепи, выбранной из группы, состоящей из SEQ ID NO: 1240 и 1305, SEQ ID NO: 1265 и 1330, SEQ ID NO: 1267 и 1332, SEQ ID NO: 1269 и 1334 и SEQ ID NO: 1276 и 1341.
10. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что каждая цепь молекулы имеет длину от 18 до 22 нуклеотидов.
11. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что дуплексная область имеет длину 19 нуклеотидов.
12. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что полинуклеотидная смысловая цепь и полинуклеотидная антисмысловая цепь соединены в виде одной цепи и образуют дуплексную область, соединенную на одном конце петлей.
13. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула имеет тупой конец.
14. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула имеет один или несколько 3'-выступающих участков.
15. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула представляет собой молекулу РНКи, активную для сайленсинга генов.
16. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула представляет собой дцРНК, киРНК, микро-РНК или кшРНК, активную для сайленсинга генов.
17. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула активна для ингибирования экспрессии GST-π.
18. Молекула нуклеиновой кислоты по п.1, отличающаяся тем, что молекула имеет IC50 для нокдауна GST-π менее чем 100 пМ.
19. Композиция, содержащая одну или несколько молекул нуклеиновой кислоты по любому из пп.1-18 и фармацевтически приемлемый носитель.
20. Композиция по п.19, отличающаяся тем, что носитель представляет собой липидную молекулу или липосому.
21. Способ лечения заболевания, ассоциированного с экспрессией GST-π, причем способ включает введение композиции по п.19 объекту, нуждающемуся в этом.
22. Способ по п.21, отличающийся тем, что заболевание представляет собой злокачественную опухоль.
23. Способ по п.22, отличающийся тем, что злокачественная опухоль присутствует в заболевании, выбранном из группы, состоящей из злокачественных опухолей, связанных с экспрессией GST, злокачественных опухолей, вызванных клетками, экспрессирующими мутантный KRAS, саркомы, фибросаркомы, злокачественной фиброзной гистиоцитомы, липосаркомы, рабдомиосаркомы, лейомиосаркомы, ангиосаркомы, саркомы Капоши, лимфангиосаркомы, синовиальной саркомы, хондросаркомы, остеосаркомы, карциномы, опухоли головного мозга, рака головы и шеи, рака молочной железы, рака легких, рака пищевода, рака желудка, рака прямой кишки, колоректального рака, рака толстой кишки, рака печени, рака поджелудочной железы, рака желчного пузыря, рака желчных протоков, рака почек, уретрального рака, рака мочевого пузыря, рака предстательной железы, рака яичек, рака полового члена, рака матки, рака яичников, рака кожи, рака кости, лейкоза, злокачественной лимфомы, эпителиальных злокачественных опухолей и неэпителиальных злокачественных опухолей.
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