RU2015133167A - Конъюгаты углевода и lna-олигонуклеотида - Google Patents

Конъюгаты углевода и lna-олигонуклеотида Download PDF

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RU2015133167A
RU2015133167A RU2015133167A RU2015133167A RU2015133167A RU 2015133167 A RU2015133167 A RU 2015133167A RU 2015133167 A RU2015133167 A RU 2015133167A RU 2015133167 A RU2015133167 A RU 2015133167A RU 2015133167 A RU2015133167 A RU 2015133167A
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conjugate
lna oligomer
antisense lna
antisense
oligomer according
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RU2015133167A
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RU2649367C2 (ru
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Нанна Альбек
Хенрик Фрюденлунн ХАНСЕН
Сюзанн КАММЛЕР
Якоб Равн
Хенрик ЭРУМ
Марк Тёрнер
Моника КРАМПЕРТ
Филипп ХАДВИГЕР
Сёрен ОТТОСЕН
Мортен Линдов
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Ф. Хоффманн-Ля Рош Аг
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Claims (28)

1. Конъюгат антисмыслового олигомера закрытых нуклеиновых кислот (LNA-олигомера), содержащий антисмысловой LNA-олигомер для применения при модулировании нуклеиновой кислоты и конъюгатную группировку, содержащую группу, направленную на асиалогликопротеиновый рецептор, ковалентно связанную с антисмысловым LNA-олигомером.
2. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором группа, направленная на асиалогликопротеиновый рецептор, выбрана из группы, состоящей из галактозы, галактозамина, N-формилгалактозамина, N-ацетилгалактозамина, N-пропионилгалактозамина, N-н-бутаноилгалактозамина и N-изобутаноилгалактозамина.
3. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором группа, направленная на асиалогликопротеиновый рецептор, не является Tyr-Glu-Glu-(аминогексилGalNAc)3 или L3G4 или кластерами галактозы на основе холана.
4. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором конъюгатная группировка также содержит модулятор фармакокинетики, выбранный из группы, состоящей из С8-С36 насыщенной или ненасыщенной жирной кислоты, стерола, холестерина, пальмитоила, гексадек-8-еноила, олеила, (9Е, 12Е)октадека-9,12-диеноила, диоктаноила и С16-С20 ацила.
5. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором конъюгатная группировка содержит кластер галактозы.
6. Конъюгат антисмыслового LNA-олигомера по п. 5, в котором кластер галактозы состоит из тримера N-ацетилгалактозамина.
7. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором конъюгатная группировка ковалентно связана с олигомером посредством расщепляемого в физиологических условиях линкера.
8. Конъюгат антисмыслового LNA-олигомера по п. 7, в котором расщепляемый в физиологических условиях линкер выбран из группы, состоящей из кислотолабильного линкера, дисульфидного линкера, сегмента нуклеозидов, связанных фосфодиэфирными связями (участка В).
9. Конъюгат антисмыслового LNA-олигомера по п. 4, где модулятор фармакокинетики присоединен к конъюгатной группировке посредством линкера, например, расщепляемого в физиологических условиях линкера.
10. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором олигонуклеотид включает в себя 7-26, например, 7-18, 7-10, 10-16, 12-14 смежных нуклеозидов.
11. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором антисмысловой LNA-олигомер представляет собой LNA-гэпмер, LNA-миксмер, LNA-тоталмер или миниатюрный LNA-олигомер.
12. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором антисмысловой LNA-олигомер содержит по меньшей мере 90% фосфоротиоатных межнуклеозидных связей.
13. Конъюгат антисмыслового LNA-олигомера по п. 1, в котором мишенью олигомера является экспрессируемая в печени нуклеиновая кислота, например, экспрессируемая в печени мРНК или микроРНК, или нуклеиновая кислота вируса.
14. Конъюгат антисмыслового LNA-олигомера по п. 13, где экспрессируемая в печени РНК представляет собой мРНК, выбранную из группы, состоящей из фактора VII, С6 компонента комплемента, Bcl2, транстиретина (TTR), PCSK9, аполипопротеина В (АроВ), рецептора глюкагона (GCGR), С-реактивного белка (CRP), диацилглицерин ацилтрансферазы 2 типа (DGAT2), глюкокортикоидного рецептора (GCCR), фосфотазы и гомолога тензина (PTEN), тирозинфосфатазы РТР1В, натрий-глюкозного котранспортера 2 типа (SGLT2) и супероксиддисмутазы SOD1 или РНК вируса, например вируса гепатита С или гепатита В.
15. Конъюгат антисмыслового LNA-олигомера по п. 13, в котором олигомер представляет собой гэпмер или более короткий олигомер.
16. Конъюгат антисмыслового LNA-олигомера по п. 13, в котором мишенью олигомера является экспрессируемая в печени микроРНК, например миР-122.
17. Конъюгат антисмыслового LNA-олигомера по п. 13, в котором длина олигомера составляет от 8 до 18 нуклеотидов.
18. Конъюгат антисмыслового LNA-олигомера по п. 1, мишенью которого является нуклеиновая кислота вируса гепатита В, например последовательность ДНК и/или РНК вируса гепатита В (HBV).
19. Конъюгат антисмыслового LNA-олигомера по любому из пп. 1-18 для применения в медицине.
20. Конъюгат антисмыслового LNA-олигомера по любому из пп. 1-18 для применения в снижении уровня экспрессируемой в печени РНК.
21. Конъюгат антисмыслового LNA-олигомера по любому из пп. 1-18 для применения при лечении метаболических заболеваний или нарушений, например заболеваний или нарушений, затрагивающих печень.
22. Конъюгат антисмыслового LNA-олигомера по пп. 16-18 для применения при лечении гепатита, например гепатита В или С.
23. Конъюгат антисмыслового LNA-олигомера по любому из пп. 1-18 для применения в изготовлении лекарственного средства для лечения заболевания или нарушения, например, указанных в любом из пп.
24. Фармацевтическая композиция, содержащая конъюгат антисмыслового LNA-олигомера по любому из пп. 1-18 и фармацевтически приемлемый разбавитель, носитель, соль или адъювант.
25. Фармацевтическая композиция по п. 24, где композиция содержит буферный солевой раствор и конъюгат антисмыслового LNA-олигомера.
26. Способ ингибирования экспрессии гена-мишени в клетке in vivo или in vitro, где указанный способ включает введение конъюгата антисмыслового LNA-олигомера по любому из пп. 1-18 в клетку, экспрессирующую указанный ген-мишень, соответственно в количестве, эффективном для снижения экспрессии гена-мишени в указанной клетке.
27. Способ ингибирования экспрессии РНК в печени индивидуума, включающий введение субъекту конъюгата антисмыслового LNA-олигомера по любому из пп. 1-18, соответственно в количестве, эффективном для снижения экспрессии гена-мишени в печени индивидуума.
28. Способ лечения заболевания или нарушения у нуждающегося в этом субъекта, включающий введение указанному субъекту фармацевтической композиции, содержащей конъюгат по любому из пп. 1-18 в терапевтически эффективном количестве.
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BR112015018161A2 (pt) 2017-08-22
US20150368642A1 (en) 2015-12-24
RU2018108405A (ru) 2019-02-26
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