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

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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»

Автор, ответственный за переписку.
Email: KochNik.KS@gmail.com
ORCID iD: 0000-0002-0096-4542

Кочергин-Никитский Константин Сергеевич - кандидат биологических наук, старший научный сотрудник, лаборатория мутагенеза.

117593,Москва, Новоясеневский проспект, 19/4-424, тел.: +7 (977) 830 94 95

Россия

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

Email: helenezak@gmail.com
ORCID iD: 0000-0002-6244-9546

Заклязьминская Елена Валерьевна - доктор медицинских наук, заведующая лабораторией медицинской генетики РНЦХ им. акад. Б.В. Петровского; доцент кафедры молекулярной и клеточной генетики медико-биологического факультета РНИМУ имени Н.И. Пирогова.

119991, Москва, Абрикосовский переулок, 2; 117997, Москва, ул. Островитянова, 1

Россия

А. В. Лавров

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

Email: alexandervlavrov@gmail.com
ORCID iD: 0000-0003-4962-6947

Лавров Александр Вячеславович - кандидат медицинских наук, ведущий научный сотрудник, лаборатория редактирования генома МГНЦ; доцент кафедры молекулярной и клеточной генетики медико-биологического факультета РНИМУ имени Н.И. Пирогова.

115522, Москва, ул. Москворечье, 1; 117997, Москва, ул. Островитянова, 1

Россия

С. А. Смирнихина

ФГБНУ «Медико-генетический научный центр»

Email: smirnikhinas@gmail.com
ORCID iD: 0000-0002-1558-3048

Смирнихина Светлана Анатольевна - кандидат медицинских наук, заведующая лабораторией редактирования генома.

115522, Москва, ул. Москворечье, 1

Россия

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