RU2012150394A - Модуляция экспрессии транстиретина - Google Patents
Модуляция экспрессии транстиретина Download PDFInfo
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Abstract
1. Соединение, включающее модифицированный олигонуклеотид, состоящий из от 12 до 30 связанных нуклеозидов, где связанные нуклеозиды содержат, по меньшей мере, 8 смежных нуклеооснований последовательности, приведенной в SEQ ID NO:80, 25, 86, 87, 115, 120, 122 или 124.2. Соединение по п.1, отличающееся тем, что модифицированный олигонуклеотид состоит из 20 связанных нуклеозидов, где связанные нуклеозиды состоят из последовательности, приведенной в SEQ ID NO:80, 25, 86, 87, 115, 120, 122 или 124.3. Соединение по п.2, отличающееся тем, что модифицированный олигонуклеотид состоит из 20 связанных нуклеозидов, где связанные нуклеозиды состоят из последовательности, приведенной в SEQ ID NO:80.4. Соединение по п.1, отличающееся тем, что модифицированный олигонуклеотид представляет собой одноцепочечный олигонуклеотид.5. Соединение по п.4, отличающееся тем, что последовательность нуклеооснований модифицированного олигонуклеотида, по меньшей мере, на 95% или 100% комплементарна SEQ ID NO 1.6. Соединение по п.1, отличающееся тем, что, по меньшей мере, одна межнуклеозидная связь представляет собой модифицированную межнуклеозидную связь.7. Соединение по п.6, отличающееся тем, что каждая межнуклеозидная связь представляет собой фосфоротиоатную межнуклеозидную связь.8. Соединение по п.1, отличающееся тем, что, по меньшей мере, один нуклеозид модифицированного олигонуклеотида содержит модифицированный сахар.9. Соединение по п.8, отличающееся тем, что, по меньшей мере, один модифицированный сахар представляет собой бициклический сахар.10. Соединение по п.9, отличающееся тем, что каждый, по меньшей мере, из одного бициклического сахара содержит 4'-(СН)-O-2' или 4'-(СН)-O-2'.11. Соединение по п.9, отличаю
Claims (25)
1. Соединение, включающее модифицированный олигонуклеотид, состоящий из от 12 до 30 связанных нуклеозидов, где связанные нуклеозиды содержат, по меньшей мере, 8 смежных нуклеооснований последовательности, приведенной в SEQ ID NO:80, 25, 86, 87, 115, 120, 122 или 124.
2. Соединение по п.1, отличающееся тем, что модифицированный олигонуклеотид состоит из 20 связанных нуклеозидов, где связанные нуклеозиды состоят из последовательности, приведенной в SEQ ID NO:80, 25, 86, 87, 115, 120, 122 или 124.
3. Соединение по п.2, отличающееся тем, что модифицированный олигонуклеотид состоит из 20 связанных нуклеозидов, где связанные нуклеозиды состоят из последовательности, приведенной в SEQ ID NO:80.
4. Соединение по п.1, отличающееся тем, что модифицированный олигонуклеотид представляет собой одноцепочечный олигонуклеотид.
5. Соединение по п.4, отличающееся тем, что последовательность нуклеооснований модифицированного олигонуклеотида, по меньшей мере, на 95% или 100% комплементарна SEQ ID NO 1.
6. Соединение по п.1, отличающееся тем, что, по меньшей мере, одна межнуклеозидная связь представляет собой модифицированную межнуклеозидную связь.
7. Соединение по п.6, отличающееся тем, что каждая межнуклеозидная связь представляет собой фосфоротиоатную межнуклеозидную связь.
8. Соединение по п.1, отличающееся тем, что, по меньшей мере, один нуклеозид модифицированного олигонуклеотида содержит модифицированный сахар.
9. Соединение по п.8, отличающееся тем, что, по меньшей мере, один модифицированный сахар представляет собой бициклический сахар.
10. Соединение по п.9, отличающееся тем, что каждый, по меньшей мере, из одного бициклического сахара содержит 4'-(СН2)-O-2' или 4'-(СН2)2-O-2'.
11. Соединение по п.9, отличающееся тем, что каждый, по меньшей мере, из одного бициклического сахара содержит мостиковую связь 4'-СН(СН3)-O-2'.
12. Соединение по п.8, отличающееся тем, что, по меньшей мере, один модифицированный сахар содержит 2'-O-метоксиэтильную группу.
13. Соединение по п.1, отличающееся тем, что, по меньшей мере, один нуклеозид содержит модифицированное нуклеооснование.
14. Соединение по п.13, отличающееся тем, что модифицированное нуклеооснование представляет собой 5-метилцитозин.
15. Соединение по п.1, отличающееся тем, что модифицированный олигонуклеотид содержит:
гэп-сегмент, состоящий из связанных дезоксинуклеозидов;
5'-боковой сегмент, состоящий из связанных нуклеозидов; и
3'-боковой сегмент, состоящий из связанных нуклеозидов;
где гэп-сегмент расположен между 5'-боковым сегментом и 3'-боковым сегментом, и где каждый нуклеозид каждого бокового сегмента содержит модифицированный сахар.
16. Соединение по п.3, отличающееся тем, что модифицированный олигонуклеотид представляет собой одноцепочечный олигонуклеотид, содержащий:
гэп-сегмент, состоящий из десяти связанных дезоксинуклеозидов;
5'-боковой сегмент, состоящий из пяти связанных нуклеозидов; и
3'-боковой сегмент, состоящий из пяти связанных нуклеозидов;
где гэп-сегмент расположен между 5'-боковым сегментом и 3'-боковым сегментом, где каждый нуклеозид каждого бокового сегмента содержит 2'-O-метоксиэтилированный сахар; и где каждый цитозин модифицированного олигонуклеотида представляет собой 5-метилцитозин, и где каждая межнуклеозидная связь модифициро ванного олигонуклеотида представляет собой фосфоротиоатную связь.
17. Композиция, содержащая соединение по любому из пп.1-16 или его соль и, по меньшей мере, один фармацевтически приемлемый носитель или разбавитель.
18. Соединение по любому из пп.1-16 для применения для лечения транстиретинового амилоидоза у человека.
19. Композиция по п.17, для применения для лечения транстиретинового амилоидоза у человека.
20. Соединение по п.18, отличающееся тем, что соединение уменьшает, по меньшей мере, что-то одно из беспокойства, отсутствия координации, нистагма, спастического парапареза, отсутствия мышечной координации, нарушения зрения, бессонницы, необычных ощущений, миоклонуса, слепоты, потери речи, кистевого туннельного синдрома, эпилептических припадков, субарахноидальных кровоизлияний, инсульта и кровотечения в головном мозге, гидроцефалии, атаксии и спастического паралича, комы, сенсорной невропатии, паратезии, гипестезии, моторной невропатии, автономной невропатии, ортостатической гипотензии, циклического запора, циклической диареи, тошноты, рвоты, пониженного потения, импотенции, замедленного опорожнения желудка, задержки мочевыделения, недержания мочи, прогрессирующей кардиопатии, усталости, одышки, потери веса, отсутствия аппетита, онемения, ощущения покалывания, слабости, увеличенного языка, нефротического синдрома, застойной сердечной недостаточности, одышки при физической нагрузке, периферического отека, аритмий, учащенного сердцебиения, ощущения головокружения, обморока, постуральной гипотензии, проблемы периферических нервов, сенсорно-двигательной недостаточности, невропатии нижних конечностей, невропатии верхних конечностей, гиперальгезии, изменения восприятия температуры, слабости в нижних конечностях, кахексии, периферического отека, гепатомегалии, пурпуры, диастолической дисфункции, экстрасистолы желудочков, черепной невропатии, ослабления глубоких сухожильных рефлексов, амилоидных отложений в стекловидном теле, помутнения стекловидного тела, сухости глаз, глаукомы, зубчатого края зрачков или отечности ног вследствие удерживания воды у человека.
21. Композиция по п.19, отличающаяся тем, что композиция уменьшает, по меньшей мере, что-то одно из беспокойства, отсутствия координации, нистагма, спастического парапареза, отсутствия мышечной координации, нарушения зрения, бессонницы, необычных ощущений, миоклонуса, слепоты, потери речи, кистевого туннельного синдрома, эпилептических припадков, субарахноидальных кровоизлияний, инсульта и кровотечения в головном мозге, гидроцефалии, атаксии и спастического паралича, комы, сенсорной невропатии, паратезии, гипестезии, моторной невропатии, автономной невропатии, ортостатической гипотензии, циклического запора, циклической диареи, тошноты, рвоты, пониженного потения, импотенции, замедленного опорожнения желудка, задержки мочевыделения, недержания мочи, прогрессирующей кардиопатии, усталости, одышки, потери веса, отсутствия аппетита, онемения, ощущения покалывания, слабости, увеличенного языка, нефротического синдрома, застойной сердечной недостаточности, одышки при физической нагрузке, периферического отека, аритмий, учащенного сердцебиения, ощущения головокружения, обморока, постуральной гипотензии, проблемы периферических нервов, сенсорно-двигательной недостаточности, невропатии нижних конечностей, невропатии верхних конечностей, гиперальгезии, изменения восприятия температуры, слабости в нижних конечностях, кахексии, периферического отека, гепатомегалии, пурпуры, диастолической дисфункции, экстрасистолы желудочков, черепной невропатии, ослабления глубоких сухожильных рефлексов, амилоидных отложений в стекловидном теле, помутнения стекловидного тела, сухости глаз, глаукомы, зубчатого края зрачков или отечности ног вследствие удерживания воды у человека.
22. Соединение по п.20, отличающееся тем, что соединение улучшает по меньшей мере, один физический симптом, по меньшей мере, один когнитивный симптом, по меньшей мере, один психиатрический симптом или, по меньшей мере, один периферический симптом транстиретинового амилоидоза.
23. Композиция по п.21, отличающаяся тем, что композиция улучшает по меньшей мере, один физический симптом, по меньшей мере, один когнитивный симптом, по меньшей мере, один психиатрический симптом или, по меньшей мере, один периферический симптом транстиретинового амилоидоза.
24. Соединение по п.22, отличающееся тем, что:
а) по меньшей мере, один из физических симптомов выбирают из группы, состоящей из беспокойства, отсутствия координации, непреднамеренно инициируемых движений, непреднамеренно незавершенных движений, неустойчивой походки, хореи, ригидности, извивающихся движений, аномального положения тела, неустойчивости, аномального выражения лица, затрудненного жевания, затрудненного глотания, затрудненного разговора, эпилептического припадка и нарушений сна;
b) по меньшей мере, один когнитивный симптом выбирают из группы, состоящей из расстройства памяти, расстройства суждения и мышления, расстройства планирования, расстройства гибкости, расстройства абстрактного мышления, расстройства уяснения правил, расстройства инициирования адекватных действий, расстройства ингибирования неадекватных действий, расстройства кратковременной памяти, расстройства длительной памяти, паранойи, дезориентации, спутанности сознания, галлюцинаций и деменции;
c) по меньшей мере, один психиатрический симптом выбирают из группы, состоящей из деменции; тревожного состояния, депрессии, притупленного аффекта, эгоцентризмов, агрессии, компульсивного поведения, раздражительности, изменений личности, включая расстройства памяти, суждения и мышления, и суицидальное мышление; или
d) по меньшей мере, один периферический симптом выбирают из группы, состоящей из уменьшенной массы головного мозга, мышечной атрофии, сердечной недостаточности, нарушенной толерантности к глюкозе, потери веса, остеопороза и тестикулярной атрофии.
25. Композиция по п.23, отличающаяся тем, что:
a) по меньшей мере, один из физических симптомов выбирают из группы, состоящей из беспокойства, отсутствия координации, непреднамеренно инициируемых движений, непреднамеренно незавершенных движений, неустойчивой походки, хореи, ригидности, извивающихся движений, аномального положения тела, неустойчивости, аномального выражения лица, затрудненного жевания, затрудненного глотания, затрудненного разговора, эпилептического припадка и нарушений сна;
b) по меньшей мере, один когнитивный симптом выбирают из группы, состоящей из расстройства памяти, расстройства суждения и мышления, расстройства планирования, расстройства гибкости, расстройства абстрактного мышления, расстройства уяснения правил, расстройства инициирования адекватных действий, расстройства ингибирования неадекватных действий, расстройства кратковременной памяти, расстройства длительной памяти, паранойи, дезориентации, спутанности сознания, галлюцинаций и деменции;
c) по меньшей мере, один психиатрический симптом выбирают из группы, состоящей из деменции; тревожного состояния, депрессии, притупленного аффекта, эгоцентризмов, агрессии, компульсивного поведения, раздражительности, изменений личности, включая расстройства памяти, суждения и мышления, и суицидальное мышление; или
d) по меньшей мере, один периферический симптом выбирают из группы, состоящей из уменьшенной массы головного мозга, мышечной атрофии, сердечной недостаточности, нарушенной толерантности к глюкозе, потери веса, остеопороза и тестикулярной атрофии.
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