RU2020127049A - Модуляторы экспрессии dnm2 - Google Patents
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Claims (44)
1. Соединение, включающее модифицированный олигонуклеотид длиной 14-30 связанных нуклеозидов, имеющий
i) последовательность нуклеооснований, содержащую по меньшей мере 14 смежных нуклеооснований SEQ ID NO: 2879;
ii) последовательность нуклеооснований, содержащую часть из по меньшей мере 14 смежных нуклеооснований, на 100% комплементарной части нуклеооснований той же длины 87359-90915; 90968-97263; 83573-87287; 3404-44737; 97378-104979; 81061-81199 или 116048-116903 из SEQ ID NO: 1,
iii) последовательность нуклеооснований, комплементарную интрону 12, интрону 13, интрону 11, интрону 1, интрону 14, экзону 10 или 3'-UTR пре-мРНК DNM2 человека или мРНК DNM2 человека, или
iv) последовательность нуклеооснований, содержащую по меньшей мере 12, по меньшей мере, 13, по меньшей мере 14 или по меньшей мере 15 смежных нуклеооснований любой из последовательностей нуклеооснований SEQ ID NO: 7-3134.
2. Соединение по п. 1, где модифицированный олигонуклеотид имеет последовательность нуклеооснований, состоящую из любой из SEQ ID NO: 2879, 2123, 2189, 2160, 3056, 2453 или 2232.
3. Соединение по п. 1 или 2, где модифицированный олигонуклеотид включает:
промежуточный сегмент, состоящий из 8-12 связанных 2'-дезоксинуклеозидов, предпочтительно 10 связанных 2'-дезоксинуклеозидов;
сегмент 5'-фланга, состоящий из 1-7 связанных нуклеозидов, предпочтительно 3 связанных нуклеозидов; и
сегмент 3'-фланга, состоящий из 1-7 связанных нуклеозидов, предпочтительно 3 связанных нуклеозидов;
где промежуточный сегмент расположен между сегментом 5'-фланга и сегментом 3'-фланга и где каждый нуклеозид концевого фланга содержит модифицированный сахар.
4. Соединение по п. 1, где модифицированный олигонуклеотид по меньшей мере на 80, 85, 90, 95 или 100% комплементарен любой из SEQ ID NO: 1, 2, 3 или 3135.
5. Соединение по любому из пп. 1-4, где модифицированный олигонуклеотид включает по меньшей мере одну модифицированную межнуклеозидную связь, предпочтительно фосфотиоатную межнуклеозидную связь.
6. Соединение по любому из пп. 1-5, где модифицированный олигонуклеотид включает по меньшей мере один бициклический сахар, предпочтительно выбранный из группы, состоящей из LNA, ENA и cEt.
7. Соединение по любому из пп. 1-6, где модифицированный олигонуклеотид включает по меньшей мере один 5-метилцитозин.
8. Соединение по любому из пп. 1-7, где соединение является одноцепочечным.
9. Соединение по любому из пп. 1-7, где соединение является двухцепочечным.
10. Соединение по любому из пп. 1-9, в котором модифицированный олигонуклеотид состоит из 16-20 связанных нуклеозидов.
11. Соединение, включающее модифицированный олигонуклеотид согласно следующей формуле: Gks Tks Tks Tds Ads Tds Tds Ads Tds Ads Gds Gds Gds mCks Tks Tk; в которой
А = аденин,
mC = 5-метилцитозин,
G = гуанин,
Т = тимин,
k = сахарный фрагмент cEt,
d = 2'-дезоксирибозил-сахарный фрагмент и
s = фосфотиоатная межнуклеозидная связь.
12. Соединение по любому из пп. 1-11, содержащее конъюгатную группу, предпочтительно где соединение состоит из модифицированного олигонуклеотида и конъюгатной группы.
13. Модифицированный олигонуклеотид по следующей химической структуре:
(SEQ ID NO: 2879) или его соль.
14. Модифицированный олигонуклеотид п. 13, который представляет собой соль натрия или соль калия.
15. Модифицированный олигонуклеотид, где анионная форма модифицированного олигонуклеотида имеет следующую химическую структуру:
(SEQ ID NO: 2879).
16. Модифицированный олигонуклеотид п. 15, где модифицированный олигонуклеотид представляет собой соль, необязательно где катион соли представляет собой натрий или калий.
17. Модифицированный олигонуклеотид по следующей химической структуре:
(SEQ ID NO: 2879).
18. Соединение, состоящее из фармацевтически приемлемой солевой формы любого из соединений по любому из пп. 1-12, предпочтительно где фармацевтически приемлемая соль представляет собой соль натрия или калиевую соль.
19. Хирально обогащенная популяция соединений по любому из пп. 1-12 или модифицированные олигонуклеотиды по любому из пп. 13-17, где популяция обогащена модифицированными олигонуклеотидами, содержащими по меньшей мере одну конкретную фосфотиоатную межнуклеозидную связь, имеющую конкретную стереохимическую конфигурацию.
20. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-12 или 18, модифицированный олигонуклеотид по любому из пп. 13-17 или популяция соединений по п. 19 и по меньшей мере один фармацевтически приемлемый разбавитель или носитель, необязательно где фармацевтически приемлемый разбавитель представляет собой фосфатно-солевой буферный раствор и необязательно где фармацевтическая композиция по существу состоит из модифицированного(ых) олигонуклеотида(ов) и фосфатно-солевого буферного раствора.
21. Соединение по любому из пп. 1-12 или 18, модифицированный олигонуклеотид по любому из пп. 13-17, популяция п. 19 или фармацевтическая композиция п. 20 для применения в терапии.
22. Соединение по любому из пп. 1-12 или 18, модифицированный олоигонуклеотид по любому из пп. 13-17, популяция по п. 19 или фармацевтическая композиция по п. 20 для применения при лечении, профилактике или уменьшении интенсивности заболевания, связанного с DNM2 у индивидуума, необязательно где заболевание представляет собой центронуклеарную миопатию, мышечную дистрофию Дюшенна или болезнь Шарко-Мари-Тута, X-сцепленную миотубулярную миопатию, аутосомно-рецессивную центронуклеарную миопатию или аутосомно-доминантную центронуклеарную миопатию и где необязательно заболевание связано с мутацией по меньшей мере в одном гене, выбранном из MTM1, BIN1 и DNM2.
23. Способ уменьшения РНК DNM2 в клетке, включающий контакт клетки с соединением по любому из пп. 1-12 или 18, модифицированным олигонуклеотидом по любому из пп. 13-17, популяцию по п. 19 или фармацевтической композицией по п. 20.
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US201862617411P | 2018-01-15 | 2018-01-15 | |
US62/617,411 | 2018-01-15 | ||
PCT/US2019/013689 WO2019140452A1 (en) | 2018-01-15 | 2019-01-15 | Modulators of dnm2 expression |
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EP (1) | EP3740575A1 (ru) |
JP (1) | JP2021511072A (ru) |
KR (1) | KR20200113214A (ru) |
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CA (1) | CA3088522A1 (ru) |
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IL (1) | IL276007A (ru) |
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MX (1) | MX2020007369A (ru) |
PE (1) | PE20211242A1 (ru) |
RU (1) | RU2020127049A (ru) |
SG (1) | SG11202006711UA (ru) |
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-
2019
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- 2019-01-15 PE PE2020000957A patent/PE20211242A1/es unknown
- 2019-01-15 AU AU2019206731A patent/AU2019206731A1/en not_active Abandoned
- 2019-01-15 MA MA051645A patent/MA51645A/fr unknown
- 2019-01-15 TW TW108101474A patent/TW201934129A/zh unknown
- 2019-01-15 RU RU2020127049A patent/RU2020127049A/ru unknown
- 2019-01-15 US US16/248,549 patent/US10865414B2/en active Active
- 2019-01-15 EP EP19703843.3A patent/EP3740575A1/en active Pending
- 2019-01-15 CN CN201980019294.3A patent/CN111902537A/zh active Pending
- 2019-01-15 JP JP2020560116A patent/JP2021511072A/ja not_active Ceased
- 2019-01-15 KR KR1020207022337A patent/KR20200113214A/ko active Search and Examination
- 2019-01-15 SG SG11202006711UA patent/SG11202006711UA/en unknown
- 2019-01-15 BR BR112020014425-8A patent/BR112020014425A2/pt not_active IP Right Cessation
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- 2019-01-15 US US16/962,136 patent/US20200392510A1/en not_active Abandoned
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2020
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TW201934129A (zh) | 2019-09-01 |
WO2019140452A1 (en) | 2019-07-18 |
CL2020001851A1 (es) | 2021-02-19 |
KR20200113214A (ko) | 2020-10-06 |
CN111902537A (zh) | 2020-11-06 |
PE20211242A1 (es) | 2021-07-09 |
MA51645A (fr) | 2020-11-25 |
US20190241896A1 (en) | 2019-08-08 |
IL276007A (en) | 2020-08-31 |
US10865414B2 (en) | 2020-12-15 |
AU2019206731A1 (en) | 2020-07-30 |
EP3740575A1 (en) | 2020-11-25 |
JP2021511072A (ja) | 2021-05-06 |
SG11202006711UA (en) | 2020-08-28 |
US20200392510A1 (en) | 2020-12-17 |
CA3088522A1 (en) | 2019-07-18 |
BR112020014425A2 (pt) | 2020-12-29 |
AU2019206731A2 (en) | 2020-10-15 |
MX2020007369A (es) | 2020-10-28 |
CO2020008769A2 (es) | 2020-10-30 |
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