medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2023.02.3-17medgen-2244Research ArticleНАУЧНЫЕ ОБЗОРЫREVIEWПрименение антисмысловых молекул для коррекции нарушений сплайсинга в терапии наследственных заболеванийThe use of antisense molecules for splicing modulation as a treatment for genetic disordersГалушкинА. С.GalushkinA. S.

Артур Сергеевич Галушкин

115522

ул. Москворечье, д. 1

Москва

Artur S. Galushkin

115522

1, Moskvorechye str.

Moscow

arthurgaluschkin@gmail.comНекрасовА. Ю.NekrasovA. Yu.

115522

ул. Москворечье, д. 1

Москва

115522

1, Moskvorechye str.

Moscow

ФГБНУ «Медико-генетический научный центр им. акад. Н. П. Бочкова»РоссияResearch Centre for Medical GeneticsRussian Federation202310042023222317Copyright © Галушкин А.С., Некрасов А.Ю., 20232023Галушкин А.С., Некрасов А.Ю.Galushkin A.S., Nekrasov A.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/2244

   Сплайсинг – сложно регулируемый этап экспрессии генов, в котором задействованы множественные цис-элементы, представленные консенсусными последовательностями пре-мРНК, а также трансэлементы – белки и рибонуклеопротеиновые комплексы. Описано множество патогенных генетических вариантов, являющихся причиной нарушения сплайсинга, и ряд исследований направлен на создание эффективных способов их коррекции. Последние работы, посвященные пониманию регуляции сплайсинга, позволили разработать несколько инструментов его коррекции для терапии наследственных заболеваний. В данном обзоре описан опыт применения конструкций на основе антисмысловых молекул in vitro и in vivo, учитывающих особенности механизма нарушения сплайсинга и задействованные элементы его регуляции, рассматриваются преимущества и недостатки применения с целью коррекции сплайсинга антисмысловых олигонуклеотидов, модифицированных малых ядерных рибонуклеопротеинов, системы модификации пре-мРНК на основе механизма транс-сплайсинга, а также способы их доставки в клетки с использованием вирусных векторов.

   Splicing is a complex stage of gene expression regulated by many cis-elements represented by the specific pre-mRNA sequence motifs and trans-elements that are proteins and ribonucleoprotein complexes. Splicing disruption often leads to genetic disorders. A lot of pathogenic variants causing aberrant splicing are described in databases for human mutations, demonstrating a need for the development of the effective and safe splicing modulation tools and its application. Recent studies of the fundamental splicing regulation processes allow researchers to develop few tools for splicing modulation in order to be used as a therapeutic. In this review we describe the experience in antisense molecules application in vitro and in vivo according to the pathogenesis of the splicing disruption and affected components of its regulation; advantages and disadvantages of antisense oligonucleotides, modified small nuclear RNAs, spliceosome-mediated mRNA trans-splicing technology as a tools of therapy and tools for its delivery to the cells are also discussed.

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The authors declare that there are no conflicts of interest present.