vedomostiregmedРегуляторные исследования и экспертиза лекарственных средствRegulatory Research and Medicine Evaluation3034-30623034-3453Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’)10.30895/1991-2919-2023-481vedomostiregmed-481Research ArticleПРЕПАРАТЫ ГЕННОЙ ТЕРАПИИGENE THERAPY DRUGSРазработка препаратов, полученных путем редактирования генома: регуляторная практикаDevelopment of Medicinal Products Based on Gene-Editing Technology: Regulatory Practiceshttps://orcid.org/0000-0002-2355-0879ПокровскийН. С.PokrovskyN. S.

Покровский Никита Станиславович

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

Nikita S. Pokrovsky

8/2 Petrovsky Blvd, Moscow 127051

pokrovsky.ns@gmail.comhttps://orcid.org/0000-0002-6008-0554ВодяковаМ. А.VodyakovaM. A.

Водякова Марина Андреевна

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

Marina A. Vodyakova

8/2 Petrovsky Blvd, Moscow 127051

vodyakova@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 Federation202320042023132-1248260Copyright © Покровский Н.С., Водякова М.А., Мельникова Е.В., Меркулов В.А., 20232023Покровский Н.С., Водякова М.А., Мельникова Е.В., Меркулов В.А.Pokrovsky N.S., Vodyakova M.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.vedomostincesmp.ru/jour/article/view/481

Новейшим подходом в генной терапии является использование систем редактирования генома соматических клеток для лечения пациентов с наследственными моногенными, онкологическими заболеваниями и инфицированных вирусом иммунодефицита человека. Редактирование генома позволяет изменить дефектный ген или провести его полное удаление с помощью систем «нуклеазы с цинковыми пальцами» (ZFN), «эффекторные нуклеазы, подобные активаторам транскрипции» (TALEN) и «короткие палиндромные повторы, регулярно расположенные группами с CRISPR-ассоциированным белком 9» (CRISPR-Cas9).

Цель работы: анализ мирового опыта и нормативных требований к разработке препаратов, полученных с использованием технологии редактирования генома постнатальных соматических клеток.

В работе описаны принципы методов редактирования генов CRISPR, ZFN, TALEN, сравнение преимуществ и недостатков каждого подхода. Разработка, производство и оценка препаратов, полученных с использованием технологий редактирования генома, так же как и этические аспекты их применения, требуют особого подхода со стороны регуляторных и законодательных органов. В настоящее время требования и рекомендации к разработке таких препаратов ограничиваются преимущественно необходимостью оценки возникновения нецелевых эффектов и рисков отложенных по времени нежелательных явлений; возможностью адаптации дизайна клинических исследований в аспекте применения суррогатных конечных точек, исключения из исследований здоровых добровольцев и групп сравнения, выбора начальной дозы для клинических исследований на основе научных данных. Кроме того, должны быть разработаны регуляторные подходы для государственной регистрации препаратов на основе систем редактирования генома.

Somatic cell genome-editing systems are the most recent gene therapy technology to treat patients with monogenic hereditary cancer or HIV. Gene editing allows for changing or completely removing a defective gene with regularly interspaced short palindromic repeat (CRISPR), zinc-finger nuclease (ZFN), and transcription activator-like effector nuclease (TALEN) systems.

The aim of the study was to analyse the existing international experience and regulatory requirements relating to the development of medicinal products based on genome editing of postnatal somatic cells.

This article describes the mechanism of action of CRISPR, ZFN, and TALEN systems and compares their advantages and disadvantages. Regulatory and legislative authorities should take a special approach to the development, manufacture, and assessment of medicinal products based on genome editing, as well as to the ethical aspects of their use. Current requirements and recommendations for the development of medicinal products based on genome editing are mostly limited to the need to evaluate the risks of off-target effects and late-onset adverse events and the possibility to adapt clinical trial design to surrogate endpoints, exclude healthy volunteers and comparison groups, and select initial doses for clinical trials based on scientific data. Thus, a regulatory approach should also be developed for the marketing authorisation of medicinal products based on genome-editing systems.

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