RU2018126545A - Композиции и способы для снижения экспрессии tau - Google Patents
Композиции и способы для снижения экспрессии tau Download PDFInfo
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Claims (28)
1. Олигонуклеотид, содержащий последовательность нуклеотидных оснований, которая по меньшей мере на 90% идентична любой из последовательностей нуклеотидных оснований, представленных в таблицах 2-17, где С в любой из последовательностей нуклеотидных оснований представляет собой либо цитозин, либо 5-метилцитозин, и где по меньшей мере один нуклеотид этого олигонуклеотида имеет 2'-модификацию.
2. Олигонуклеотид по п. 1, где указанный олигонуклеотид содержит последовательность нуклеотидных оснований, которая по меньшей мере на 90% идентична любой из последовательностей, представленных в таблицах 2-8, где С в любой из последовательностях нуклеотидных оснований представляет собой либо цитозин, либо 5-метилцитозин, и где каждый нуклеотид этого олигонуклеотида имеет 2'-модификацию.
3. Олигонуклеотид по п. 2, где указанный олигонуклеотид содержит последовательность нуклеотидных оснований, которая по меньшей мере на 90% идентична любой из последовательностей, представленным в таблицах 2-8, или по меньшей мере на 95% идентична любой из последовательностей, представленных в таблицах 2-8, или предпочтительно содержит любую из последовательностей, представленных в Таблицах 2-8.
4. Олигонуклеотид по любому из пп. 2, 3, где межнуклеозидной связью олигонуклеотида является фосфодиэфирная или фосфортиоатная связь.
5. Олигонуклеотид по любому из пп. 2-4, где указанный олигонуклеотид содержит линкер, присоединенный к 3'-концу олигонуклеотида посредством фосфатного мостика, и где указанный олигонуклеотид имеет любую из следующих структур:
6. Олигонуклеотид по любому из пп. 2-5, где указанный олигонуклеотид снижает уровень экспрессии мРНК или белка tau независимо от РНКазы Н.
7. Олигонуклеотид по п. 1, где указанный олигонуклеотид содержит последовательность нуклеотидных оснований, которая по меньшей мере на 90% или по меньшей мере на 95% идентична, или содержит, или состоит из любой из последовательностей нуклеотидных оснований, представленных в таблицах 9-15 и 17, где С в любой из последовательностей нуклеотидных оснований представляет собой либо цитозин, либо 5-метилцитозин, и где по меньшей мере один нуклеотид этого олигонуклеотида имеет 2'-модификацию.
8. Олигонуклеотид по п. 7, где межнуклеозидной связью олигонуклеотида является фосфортиоатная связь.
9. Олигонуклеотид по любому из пп. 7, 8, где олигонуклеотид содержит по меньшей мере пять смежных 2'-дезоксинуклеозидов, предпочтительно, по меньшей мере семь смежных 2'-дезоксинуклеозидов, более предпочтительно, по меньшей мере десять смежных 2'-дезоксинуклеозидов.
10. Олигонуклеотид по любому из пп. 7-9, где указанный олигонуклеотид снижает уровень экспрессии мРНК или белка tau под действием активирующей РНКазы Н.
11. Олигонуклеотид по любому из пп. 1-10, где каждый С в любых последовательностях нуклеотидных оснований представляет собой 5-метилцитозин.
12. Олигонуклеотид, содержащий последовательность нуклеотидных оснований, которая комплементарна по меньшей мере 12 смежным нуклеотидным основаниям любой из SEQ ID NOs: 487-506, где по меньшей мере один нуклеотид этого олигонуклеотида имеет 2'-модификацию.
13. Олигонуклеотид по п. 12, где олигонуклеотид содержит последовательность нуклеотидных оснований, которая на 100% комплементарна по меньшей мере 12 смежным нуклеотидным основаниям любой из SEQ ID NOs: 487-506.
14. Олигонуклеотид по п. 12 или 13, где указанный олигонуклеотид содержит один или более 5-метилцитозинов.
15. Олигонуклеотид по любому из пп. 12-14, где каждый нуклеотид этого олигонуклеотида имеет 2'-модификацию.
16. Олигонуклеотид по любому из пп. 12-15, где указанный олигонуклеотид содержит по меньшей мере пять смежных 2'-дезоксинуклеозидов, предпочтительно, по меньшей мере семь смежных 2'-дезоксинуклеозидов, более предпочтительно, по меньшей мере десять смежных 2'-дезоксинуклеозидов.
17. Олигонуклеотид по любому из пп. 1-16, где указанный олигонуклеотид содержит 12-30 нуклеотидных оснований, предпочтительно, 12-25 нуклеотидных оснований, более предпочтительно, 15-20 нуклеотидных оснований.
18. Олигонуклеотид по любому из пп. 1-17, где 2'-модификация выбрана из группы, состоящей из 2'-фтора, 2'-дезокси-2'-фтора, 2'-О-метила, 2'-О-метоксиэтила (2'-О-МО), 2'-О-аминопропила (2'-О-AP), 2'-О-диметиламиноэтила (2'-О-DMAOE), 2'-О-диметиламинопропила (2'-О-DMAP), 2'-О-диметиламиноэтилоксиэтила (2'-О-DMAEOE) и 2'-О-N-метилацетамидо (2'-О-NMA).
19. Олигонуклеотид по любому из пп. 1-18, где 2'-модификацией является 2'-О-метоксиэтил (2'-О-MOE).
20. Олигонуклеотид по любому из пп. 1-19, где олигонуклеотид обладает способностью снижать уровень экспрессии мРНК или белка tau по меньшей мере на 30% in vitro или по меньшей мере на 30% in vivo.
21. Композиция, содержащая олигонуклеотид по любому из пп. 1-20 и фармацевтически приемлемый носитель.
22. Применение олигонуклеотида по любому из пп. 1-20 для лечения tau-ассоциированного заболевания у индивидуума, нуждающегося в этом.
23. Применение по п. 22, где tau-ассоциированное заболевание выбрано из болезни Альцгеймера (БА), амиотрофического бокового склероза/комплекса паркинсонизм-деменция (АБС-КПД), деменции в области аргирофильных зерен (ДАГЗ), амилоидной ангиопатии британского типа, церебральной амилоидной ангиопатии, хронической травматической энцефалопатии (ХТЭ), кортикобазальной дегенерации (КБД), болезни Крейцфельда-Якоба (БКЯ), деменции боксеров, диффузных повреждений нейрофибриллярных клубков с кальцификацией, синдрома Дауна, синдрома Дравета, эпилепсии, деменции в области лобно-височной доли (ДЛВД), деменции в области лобно-височной доли, ассоциированной с паркинсонизмом, сцепленным с хромосомой 17 (FTDP-17), дегенерации передней лобно-височной доли, ганглиоглиомы, ганглиоцитомы, болезни Герстманна-Штраусслера-Шейнкера, болезни Галервордена-Шпатца, болезни Гентингтона, миозита, вызываемого тельцами включения, энцефалопатии, вызываемой свинцом, болезни Литико-Бодига, менингиоангиоматоза, атрофии многих органов, миотонической дистрофии, болезни Нимана-Пика типа С (НП-С), не-гваманиевомого заболевания двигательных нейронов, ассоциированного с поражением нейрофибриллярных клубков, болезни Пика (БП), постэнцефалитного паркинсонизма, церебральной амилоидной ангиопатии, вызываемой белками прионами, прогрессирующего субкортикального глиоза, прогрессирующего надъядерного паралича (ПНП), подострого склерозирующего панэнцефалита, деменции, поражающей только область клубков, деменции, преобладающей в области клубков, мультиинфарктной деменции, ишемического инсульта или клубневого склероза.
24. Олигонуклеотид по п. 7, где указанный олигонуклеотид содержит любую из последовательностей нуклеотидных оснований, представленные в таблицах 9-15 и 17, где каждый из 1-5 нуклеотидов содержит 2'-О-MOE-модифицированный нуклеозид, каждый из 6-15 нуклеотидов содержит 2'-дезоксинуклеозид, а каждый из 16-20 нуклеотидов содержит 2'-О-MOE-модифицированный нуклеозид.
25. Олигонуклеотид, содержащий последовательность нуклеотидных оснований, выбранную из любых SEQ ID NN: 208, 284, 285, 313, 329, 335, 366, 384, 386, 405, 473 и 474.
26. Олигонуклеотид по п. 25, где каждый из 1-5 нуклеотидов содержит 2'-О-MOE-модифицированный нуклеозид, каждый из 6-15 нуклеотидов содержит 2'-дезоксинуклеозид, а каждый из 16-20 нуклеотидов содержит 2'-О-MOE-модифицированный нуклеозид.
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