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Кардиомиопатии, ассоциированные с мутациями гена десмина: молекулярный патогенез и генотерапевтические подходы

https://doi.org/10.18786/2072-0505-2019-47-025

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Аннотация

Кардиомиопатия – широко распространенная группа заболеваний сердечно-сосудистой системы. Генетически обусловленные кардиомиопатии связывают с  нарушениями более чем в 100 различных генах, в том числе в гене DES, кодирующем белок десмин  – один из основных белков промежуточных филаментов, обеспечивающих структурную и функциональную целостность миоцитов. Мутации в  гене DES приводят к  развитию десминзависимых кардиомиопатий, характеризующихся высокой степенью тяжести течения и неблагоприятным прогнозом. До настоящего времени специфического лечения кардиомиопатии не разработано. Имеющиеся консервативные и хирургические подходы направлены на замедление темпов прогрессирования сердечной недостаточности и  профилактику внезапной сердечной смерти, но их эффективность ограничена. Развитие методов генотерапии и  геномного редактирования может способствовать созданию эффективных методов этиотропной терапии десминопатий. Опубликован ряд работ, посвященных применению методов генотерапии при кардиомиопатиях различной генетической природы, включая ассоциированные с мутациями в гене DES. В области терапии десминопатий методы геномного редактирования пока не используются. Тем не менее многообещающие результаты получены при использовании систем редактирования CRISPR/Cas9 и  TALEN для коррекции “gain-of-function” мутаций в  некоторых других генах, таких как MYBPC3 и PLN. Имеются данные, указывающие на возможность улучшения симптоматики десминзависимой кардиомиопатии, вплоть до бессимптомного течения после нокаута мутантного аллеля с сохранением функции белка за счет экспрессии только нормального аллеля. Мы считаем, что подходы, основанные на технологии геномного редактирования, представляют собой перспективное направление для разработки эффективных специфических методов лечения десминопатий.

Об авторах

К. С. Кочергин-Никитский
ФГБНУ «Медико-генетический научный центр»
Россия

науч. сотр., лаборатория мутагенеза,

115522, г. Москва, ул. Москворечье, 1

117593, г. Москва, Новоясеневский проспект, 19/4–424



Е. В. Заклязьминская
ФГБНУ «Российский научный центр хирургии им. акад. Б.В. Петровского»; ФГБОУ ВО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздрава России
Россия

д-р мед. наук, заведующая лабораторией медицинской генетики, 119991, г. Москва, Абрикосовский переулок, 2;

доцент кафедры молекулярной и клеточной генетики медико-биологического факультета, 117997, г. Москва, ул. Островитянова, 1



А. В. Лавров
ФГБНУ «Медико-генетический научный центр»; ФГБОУ ВО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздрава России
Россия

канд. мед. наук, вед. науч. сотр., лаборатория редактирования генома, 115522, г. Москва, ул. Москворечье, 1;

доцент кафедры молекулярной и клеточной генетики медико-биологического факультета, 117997, г. Москва, ул. Островитянова, 1



С. А. Смирнихина
ФГБНУ «Медико-генетический научный центр»
Россия

 канд. мед. наук, заведующая лабораторией редактирования генома,

115522, г. Москва, ул. Москворечье, 1



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Для цитирования:


Кочергин-Никитский К.С., Заклязьминская Е.В., Лавров А.В., Смирнихина С.А. Кардиомиопатии, ассоциированные с мутациями гена десмина: молекулярный патогенез и генотерапевтические подходы. Альманах клинической медицины. 2019;47. https://doi.org/10.18786/2072-0505-2019-47-025

For citation:


Kochergin-Nikitsky K.S., Zaklyazminskaya E.V., Lavrov A.V., Smirnikhina S.A. Cardiomyopathies associated with the DES gene mutations: molecular pathogenesis and gene therapy approaches. Almanac of Clinical Medicine. 2019;47. (In Russ.) https://doi.org/10.18786/2072-0505-2019-47-025

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