RU2017108757A - Лечение связанных с геном-супрессором опухолей заболеваний посредством ингибирования природного транскрипта в антисмысловой ориентации относительно этого гена - Google Patents

Лечение связанных с геном-супрессором опухолей заболеваний посредством ингибирования природного транскрипта в антисмысловой ориентации относительно этого гена Download PDF

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RU2017108757A
RU2017108757A RU2017108757A RU2017108757A RU2017108757A RU 2017108757 A RU2017108757 A RU 2017108757A RU 2017108757 A RU2017108757 A RU 2017108757A RU 2017108757 A RU2017108757 A RU 2017108757A RU 2017108757 A RU2017108757 A RU 2017108757A
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disease
polynucleotide
tumor suppressor
suppressor gene
seq
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RU2746478C2 (ru
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Джозеф КОЛЛАРД
ШЕРМАН Ольга ХОРЬКОВА
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КьюРНА, Инк.
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Claims (14)

1. Способ повышения экспрессии полинуклеотида гена-супрессора опухолей в клетках или тканях пациента in vivo или in vitro, включающий контактирование указанных клеток или тканей с по меньшей мере одним антисмысловым олигонуклеотидом длиной от 19 до 30 нуклеотидов, который избирательно направлен на природный антисмысловой полинуклеотид полинуклеотида гена-супрессора опухолей, причем указанный по меньшей мере один олигонуклеотид выбран из группы, состоящей из SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12 или SEQ ID NO: 13, посредством чего осуществляется повышение экспрессии полинуклеотида гена-супрессора опухолей в клетках или тканях пациента in vitro, где полинуклеотид гена-супрессора опухолей кодирует Р53 или Р73.
2. Синтетический, модифицированный олигонуклеотид для повышения экспрессии полинуклеотида гена-супрессора опухолей in vivo, где полинуклеотид гена-супрессора опухолей кодирует Р53 или Р73 и указанный по меньшей мере один олигонуклеотид имеет по меньшей мере 90% комплементарность природному антисмысловому полинуклеотиду, выбранному из группы, состоящей из SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12 или SEQ ID NO: 13, где указанный олигонуклеотид дополнительно включает по меньшей мере одну модификацию, причем по меньшей мере одну модификацию выбирают из по меньшей мере одной модифицированной молекулы сахара, по меньшей мере одной модифицированной межнуклеотидной связи, по меньшей мере одного модифицированного нуклеотида и их комбинаций.
3. Олигонуклеотид по п. 2, в котором по меньшей мере одна модификация включает межнуклеотидную связь, выбираемую из группы, состоящей из фосфоротиоата, алкилфосфоната, фосфородитиоата, алкилфосфонотиоата, фосфорамидата, карбамата, карбоната, триэфира фосфорной кислоты, ацетамидата, карбоксиметилового эфира и их комбинаций.
4. Олигонуклеотид по п. 2, который включает по меньшей мере одну фосфоротиоатную межнуклеотидную связь.
5. Олигонуклеотид по п. 2, который включает остов из фосфоротиоатных межнуклеотидных связей.
6. Олигонуклеотид по п. 2, который включает по меньшей мере один модифицированный нуклеотид, выбираемый из пептидонуклеиновой кислоты, замкнутой нуклеиновой кислоты (LNA), их аналога, производного и комбинаций.
7. Олигонуклеотид по п. 2, который включает множество модификаций, причем указанные модификации включают межнуклеотидные связи, выбираемые из фосфоротиоата, алкилфосфоната, фосфородитиоата, алкилфосфонотиоата, фосфорамидата, карбамата, карбоната, триэфира фосфорной кислоты, ацетамидата, карбоксиметилового эфира и их комбинации.
8. Олигонуклеотид по п. 2, который включает множество модификаций, причем указанные модификации включают модифицированные нуклеотиды, выбираемые из пептидонуклеиновых кислот, замкнутых нуклеиновых кислот (LNA), их аналогов, производных и комбинаций.
9. Олигонуклеотид по п. 2, который включает по меньшей мере одну модифицированную молекулу сахара, выбираемую из 2'-O-метоксиэтил-модифицированной молекулы сахара, 2'-метокси-модифицированной молекулы сахара, 2'-O-алкил-модифицированной молекулы сахара, молекулы бициклического сахара и их комбинации.
10. Олигонуклеотид по п. 2, который включает множество модификаций, причем указанные модификации включают модифицированные молекулы сахара, выбираемые из 2'-O-метоксиэтил-модифицированной молекулы сахара, 2'-метокси-модифицированной молекулы сахара, 2'-O-алкил-модифицированной молекулы сахара, молекулы бициклического сахара и их комбинации
11. Композиция для повышения экспрессии полинуклеотида гена-супрессора опухолей в клетках или тканях пациента in vivo или in vitro, включающая один или несколько олигонуклеотидов по п.2 и фармацевтически приемлемый эксципиент..
12. Композиция по п. 11, где указанный один или несколько олигонуклеотидов включает одну или несколько модификаций, выбранных из фосфоротиоата, метилфосфоната, пептидонуклеиновой кислоты, молекул замкнутых нуклеиновых кислот (LNA) и их комбинаций.
13. Способ профилактики или лечения заболевания, связанного с по меньшей мере одним полинуклеотидом гена-супрессора опухолей и/или по меньшей мере одним кодируемым им продуктом, где полинуклеотид гена-супрессора опухолей кодирует Р53 или Р73, включающий введение пациенту терапевтически эффективной дозы по меньшей мере одного антисмыслового олигонуклеотида по пункту 2, который связывается с природной антисмысловой последовательностью указанного по меньшей мере одного полинуклеотида гена-супрессора опухолей и повышает экспрессию указанного по меньшей мере одного полинуклеотида гена-супрессора опухолей; посредством чего осуществляется профилпктика или лечение заболевания, связанного с по меньшей мере одним полинуклеотидом гена-супрессора опухолей и/или по меньшей мере одним кодируемым им продуктом.
14. Способ по п. 13, в котором заболевание, связанное с по меньшей мере одним полинуклеотидом гена-супрессора опухолей, выбирают из заболевания, связанного со сниженным или повышенным апоптозом, старения тканей/клеток, рака (в том числе злокачественных опухолей, приведенных в таблице 1), аутоиммунного заболевания, болезни иммунодефицита, включающей СПИД, физиологического старения, нейродегенеративного заболевания или нарушения (болезни Альцгеймера, атаксии-телеангиэктазии, болезни Паркинсона, бокового амиотрофического склероза, болезни Хантингтона и т.д.), гиперпластического заболевания (келоида), ревматоидного артрита, коронарной болезни сердца, ишемической гибели клеток, лимфопролиферативного нарушения, атеросклероза, остеопороза, миелодиспластического синдрома, вызванного токсином заболевания, вирусной инфекции, заживления раны, болезни Каудена (CD), болезни Лермитта-Дуклоса (LDD), синдрома Баннайана-Зонана (BZS, также известного как синдром Баннайана-Райли-Рувалкаба, синдром Рувалкаба-Мири-Смита и синдром Райли-Смита), трансплантации, связанного с апоптозом заболевания или нарушения, болезни обмена веществ или метаболического состояния (диабета), болезней или нарушений почки, инфаркта миокарда/сердечной недостаточности, ишемии, сепсиса, воспалительного заболевания, при котором преобладают конкретные гемопоэтические клетки, пролиферативного заболевания или заболевания или нарушения, в случае которого примером терапии является лечение воспалительного заболевания через увеличение апоптоза.
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