RU2487716C2 - Новые структуры малых интерферирующих рнк (sirna) - Google Patents

Новые структуры малых интерферирующих рнк (sirna) Download PDF

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RU2487716C2
RU2487716C2 RU2010113514/10A RU2010113514A RU2487716C2 RU 2487716 C2 RU2487716 C2 RU 2487716C2 RU 2010113514/10 A RU2010113514/10 A RU 2010113514/10A RU 2010113514 A RU2010113514 A RU 2010113514A RU 2487716 C2 RU2487716 C2 RU 2487716C2
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compound according
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sequence
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nucleotide
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Елена Фейнштейн
Хусейн АЙГУН
Рами СКАЛИТЕР
Хагар Калински
Игорь Метт
Джеймс МАКСВИГГЕН
Леонид Бейгельман
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Кварк Фармасьютикалс, Инк.
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Abstract

Изобретение относится к области молекулярной биологии. Предложено соединение siRNA для лечения или предотвращения возникновения заболевания, связанного с экспрессией целевого гена, содержащего новые последовательности и структурные мотивы, которые подавляют экспрессию специфических генов человека, а также фармацевтическая композиция, включающая такое соединение и фармацевтически приемлемый носитель, и способ лечения. Изобретение может быть использовано в медицине для целей терапии заболеваний, связанных с нарушением генной экспрессии. 3 н. и 17 з.п. ф-лы, 23 ил., 1 табл., 21 пр.

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Claims (20)

1. Соединение для лечения или предотвращения возникновения или тяжести заболевания или патологического состояния, связанного с экспрессией целевого гена, причем указанное соединение имеет следующую двухцепочечную структуру:
5' (N)х-Z 3'(антисмысловая цепь)
3' Z'-(N')y-z'' 5'(смысловая цепь),
где (N)x включает по меньшей мере пять чередующихся модифицированных рибонуклеотидов, начиная с 3' конца, и по меньшей мере девять модифицированных рибонуклеотидов в целом, причем каждый такой модифицированный рибонуклеотид содержит 2'-0-метил в своей углеводной части, а каждый из оставшихся N представляет собой немодифицированный рибонуклеотид или нестандартный фрагмент;
где в (N')y по меньшей мере один N' в положениях 15, 16, 17 или 18 представляет собой нестандартный фрагмент, причем указанный нестандартный фрагмент выбран из группы, состоящей из остатка рибозы, лишенного азотистого основания, остатка дезоксирибозы, лишенной азотистого основания, модифицированного или немодифицированного дезоксирибонуклеотида, зеркального нуклеотида и нуклеотида, присоединенного к соседнему нуклеотиду посредством 2'-5' межнуклеотидной фосфатной связи; и каждый из оставшихся N' представляет собой рибонуклеотид, который может быть немодифицированным или модифицированным, или представлять собой нестандартный фрагмент;
причем каждый из (N)x и (N')y представляет собой олигорибонуклеотид, в котором каждый последовательный N или N' присоединен к следующему N или N' посредством ковалентной связи,
причем Z и Z' может присутствовать или отсутствовать, но если присутствует, то независимо представляет собой 1-5 последовательных нуклеотидов, ковалентно присоединенных на 3'-конце цепи, в которой присутствует;
причем z'' представляет собой кэппирующую группу, ковалентно присоединенную к 5' концу (N')y;
где x=y=19;
причем последовательность (N)x, по существу, комплементарна последовательности (N')y; и
причем последовательность (N')y идентична последовательности мРНК, кодируемой указанным целевым геном.
2. Соединение по п.1, при этом по меньшей мере один нестандартный фрагмент в N' представляет собой закрытую нуклеиновую кислоту (LNA).
3. Соединение по п.1, при этом Z и Z' отсутствуют.
4. Соединение по п.1, при этом z'' присутствует.
5. Соединение по п.4, при этом z'' выбран из группы, состоящей из остатка рибозы, лишенного азотистого основания, остатка дезоксирибозы, лишенного азотистого основания, инвертированного фрагмента рибозы, лишенного азотистого основания, фрагмента дезоксирибозы, С6-амино-Pi и зеркального нуклеотида, выбранного из группы, состоящей из L-ДНК (L-дезоксирибоаденозин-3'-фосфата) - зеркального dA; L-дезоксирибоцитидин-3'-фосфата (зеркального dC); L-дезоксирибогуанозин-3'-фосфата (зеркального dG); L-дезоксириботимидин-3'-фосфат (зеркального отображения dT) и L-PHK (L-рибоаденозин-3'-фосфата) - зеркального rA; L-рибоцитидин-3'-фосфата (зеркального rC); L-рибогуанозин-3'-фосфата (зеркального rG); и L-рибоурацил-3'-фосфата (зеркального dU).
6. Соединение по п.5, при этом z'' представляет собой инвертированный фрагмент дезоксирибонуклеотида, лишенного азотистого основания.
7. Соединение по п.1, при этом по меньшей мере один нестандартный фрагмент в (N')y представляет собой зеркальный нуклеотид.
8. Соединение по п.7, при этом зеркальный нуклеотид присутствует в положении 17, положении 18 или положениях 17 и 18.
9. Соединение по п.8, при этом зеркальный нуклеотид присутствует в положении 18.
10. Соединение по любому из пп.8 или 9, при этом оставшиеся рибонуклеотиды являются немодифицированными.
11. Соединение по любому из пп.1, 8 или 9, при этом (N)x включает модифицированные рибонуклеотиды, содержащие 2'-O-метил в углеводной части, в положениях 2, 4, 6, 8, 11, 13, 15, 17 и 19, и каждый из оставшихся N представляет собой немодифицированный рибонуклеотид.
12. Соединение по п.10, при этом (N)x включает модифицированные рибонуклеотиды, содержащие 2'-O-метил в углеводной части в положениях 2, 4, 6, 8, 11, 13, 15, 17 и 19, и каждый из оставшихся N представляет собой немодифицированный рибонуклеотид.
13. Соединение по п.1, при этом по меньшей мере один нестандартный фрагмент в (N')y представляет собой нуклеотид, присоединенный к соседнему нуклеотиду посредством 2'-5' межнуклеотидной фосфатной связи.
14. Соединение по п.13, при этом нуклеотид, присоединенный к соседнему нуклеотиду посредством 2'-5' межнуклеотидной фосфатной связи, присутствует в положениях 16, 17, 18, 16-17, 17-18 или 16-18.
15. Соединение по п.1, при этом последовательность (N')y, по существу, идентична последовательности мРНК, кодируемой целевым геном CASP2 (SEQ ID NO:10 или SEQ ID NO:11).
16. Соединение по п.15, при этом последовательность (N)x включает последовательность, представленную одной из SEQ ID NOS: 134, 136, 138, 140, 87154, 87156, 87158, 87160, 87162, 87164, 87166, 87168, 87170, 87172, 87174, 87176 или 87178.
17. Соединение по п.16, при этом последовательность (N')y включает последовательность, представленную одной из SEQ ID NOS: 133, 135, 137, 139, 87153, 87155, 87157, 87159, 87161, 87163, 87165, 87167, 87169, 87171, 87173, 87175 или 87177.
18. Соединение по п.17, при этом последовательность (N)x включает SEQ ID NO:140, а последовательность (N')y включает SEQ ID NO:139.
19. Композиция, содержащая соединение по п.1 и фармацевтически приемлемый носитель, применяемая в эффективном количестве для подавления экспрессии целевого гена у субъекта, который в этом нуждается.
20. Способ лечения или предотвращения возникновения или тяжести заболевания или патологического состояния у субъекта, нуждающегося в этом, где заболевание или патологическое состояние и/или связанные с ними симптомы выбирают из группы, состоящей из следующих: потеря слуха, острая почечная недостаточность (ОПН), глаукома, острый респираторный дистресс-синдром (ОРДС) и другие острые легочные и респираторные повреждения, ишемически-реперфузионные повреждения, сопровождающие трансплантацию легких, глазные ишемические состояния, включая переднюю ишемическую оптическую нейропатию; пересадка органов, включая трансплантацию легких, печени, сердца, поджелудочной железы и почек, и включая ОФТ (отсроченную функцию трансплантата), нефро- и нейротоксичность, повреждения спинного мозга, пролежни, возрастная макулярная дистрофия (ВМД), синдром сухих глаз, ишемическая окулярная невропатия (ИОН), мукозит слизистой оболочки рта и хроническое обструктивное заболевание легких (ХОБЛ), включающий введение субъекту фармацевтической композиции по п.19 в количестве, эффективном для предотвращения или лечения указанного заболевания или патологического состояния.
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AU2008306455B2 (en) 2013-08-22
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US20130123334A1 (en) 2013-05-16
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