biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2023-23-3-247-261biopreparat-499Research ArticleОБЗОРЫREVIEWSАктуальные направления и риски применения препаратов на основе технологий редактирования геномаCurrent trends and risks associated with the use of therapies based on genome editinghttps://orcid.org/0000-0001-8377-9205РачинскаяО. А.RachinskayaO. A.

Рачинская Ольга Анатольевна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

 

Olga A. Rachinskaya, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

Rachinskaya@expmed.ruhttps://orcid.org/0000-0002-9585-3545МельниковаЕ. В.MelnikovaE. V.

Мельникова Екатерина Валерьевна, канд. биол. наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Ekaterina V. Melnikova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

melnikovaEV@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, д-р мед. наук, проф.

Петровский б-р, д. 8, стр. 2, Москва, 127051; 

Трубецкая ул., д. 8, стр. 2, Москва, 119991

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

8/2 Trubetskaya St., Moscow 119991

merkulov@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации;  Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И.М. Сеченова» (Сеченовский Университет) Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal Products; I. M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202327072023233247261Copyright © Рачинская О.А., Мельникова Е.В., Меркулов В.А., 20232023Рачинская О.А., Мельникова Е.В., Меркулов В.А.Rachinskaya O.A., Melnikova E.V., Merkulov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/499Актуальность

Актуальность. В настоящее время разработано множество различных подходов к редактированию генома, основанных на применении разных систем редактирования, осуществлении модификаций генома с образованием одноцепочечных или двухцепочечных разрывов ДНК, in vivo или ex vivo, с восстановлением последовательности генома с помощью гомологичной рекомбинации или негомологичного соединения концов ДНК. Однако применение систем редактирования генома сопряжено с возможным возникновением целого ряда рисков, вследствие сложной биологии таких препаратов и фундаментального значения цели их воздействия – молекулы ДНК.

Цель

Цель. Анализ актуальных направлений и рисков, связанных с применением препаратов на основе систем редактирования генома, способов снижения рисков и методов их исследования, используемых для выявления и контроля возникновения нежелательных эффектов.

Обсуждение

Обсуждение. Анализ данных литературы показал, что нежелательные эффекты от применения препаратов на основе систем редактирования генома могут быть связаны как со способами доставки компонентов системы в клетку, так и с функциональной активностью самой системы (недостаточное целевое или нежелательное нецелевое действия). В обзоре обозначены основные риски при использовании систем редактирования генома. Установлено, что для снижения рисков применения систем редактирования генома предпочтительно проведение репарации разрывов ДНК путем гомологичной рекомбинации, использование обладающих большей специфичностью и точностью рестрикции систем редактирования генома и эндонуклеаз в их составе, увеличение специфичности гРНК (для CRISPR/Cas), контролируемая коррекция активности элементов системы регуляции клеточного цикла и апоптоза, регуляция продолжительности экспрессии и персистенции компонентов систем редактирования генома в клетках и др.

Заключение

Заключение. Освещение основных рисков, связанных с применением этой группы препаратов, является актуальным в связи с необходимостью предоставления данных в регистрационном досье на высокотехнологичный лекарственный препарат, касающихся оценки качества, эффективности и безопасности.

Scientific relevance

Scientific relevance. To date, multiple approaches to genome editing have been developed based on different genome-editing systems (GESs) and genome modifications that result in single- or double-strand DNA breaks, either in vivo or ex vivo, followed by homologous recombination or non-homologous end joining to restore the sequence. However, the use of GESs is associated with a number of potential risks arising from the complex biology of such medicinal products and the fundamental role of their target, i.e. the DNA molecule.

Aim

Aim. This study analysed the most relevant trends and risks associated with medicinal products based on genome editing, the ways taken to overcome these risks, and the research methods used to identify and control the development of undesirable effects.

According to the literature, the adverse effects of GESs may arise both from the methods used to deliver GES components into the cell and from the functional activity of the GES itself, which includes insufficient on-target or undesirable off-target effects. This review indicates the main risks associated with the use of GESs. Preferable strategies to mitigate the risks of using GESs include repairing DNA breaks by homologous recombination, selecting GESs and related endonucleases that have greater specificity and restriction accuracy, increasing guide RNA specificity (for CRISPR/Cas), correcting the activity of the system regulating the cell cycle and apoptosis in a controlled manner, regulating the duration of expression and persistence of GES components in cells, etc.

Conclusions

Conclusions. The requirement to include quality, efficacy, and safety data when submitting registration dossiers for advanced therapy medicinal products prompts the discussion of the main risks associated with such products.

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