biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2026-26-2-144-158biopreparat-784Research ArticleТЕМА НОМЕРА: РАЗРАБОТКА ПРЕПАРАТОВ ДЛЯ ЛЕЧЕНИЯ РЕДКИХ (ОРФАННЫХ) ЗАБОЛЕВАНИЙISSUE TOPIC: DEVELOPMENT OF MEDICINAL PRODUCTS FOR THE TREATMENT OF RARE (ORPHAN) DISEASESДоклиническая разработка педиатрических орфанных генотерапевтических препаратов: анализ подходов и проблем (обзор)Preclinical development of pediatric orphan gene therapy medicinal products: Analysis of approaches and challenges (review)https://orcid.org/0000-0002-2901-732XАзароваА. М.AzarovaA. M.

Азарова Анна Михайловна, канд. биол. наук

Ул. Заводская, стр. 273, пос. Вольгинский, городской округ Покров, Владимирская область, 601125

Anna M. Azarova, Cand. Sci. (Biol.)

273 Zavodskaya St., Volginsky, Pokrov, Vladimir Region 601125

amazarova@generium.ruhttps://orcid.org/0000-0003-4624-9189ГавриловаН. А.GavrilovaN. A.

Гаврилова Наталья Андреевна, канд. биол. наук

Ул. Заводская, стр. 273, пос. Вольгинский, городской округ Покров, Владимирская область, 601125

Natalia A. Gavrilova, Cand. Sci. (Biol.)

273 Zavodskaya St., Volginsky, Pokrov, Vladimir Region 601125

https://orcid.org/0009-0009-0762-6325ТихомироваМ. В.TikhomirovaM. V.

Тихомирова Мария Васильевна

Ул. Заводская, стр. 273, пос. Вольгинский, городской округ Покров, Владимирская область, 601125

Mariia V. Tikhomirova

273 Zavodskaya St., Volginsky, Pokrov, Vladimir Region 601125

Акционерное общество «ГЕНЕРИУМ»РоссияGENERIUM JSCRussian Federation202604072026262144158Copyright © Азарова А.М., Гаврилова Н.А., Тихомирова М.В., 20262026Азарова А.М., Гаврилова Н.А., Тихомирова М.В.Azarova A.M., Gavrilova N.A., Tikhomirova M.V.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/784ВВЕДЕНИЕ

ВВЕДЕНИЕ. Отсутствие единых регуляторных требований к доклиническим исследованиям (ДКИ) педиатрических орфанных генотерапевтических лекарственных препаратов (ГТЛП) затрудняет их разработку и регистрацию. В обзоре систематизированы основные особенности ДКИ таких препаратов и проанализирован успешный опыт двух зарегистрированных ГТЛП для обоснования подходов к ускорению вывода новых препаратов на рынок.

ЦЕЛЬ

ЦЕЛЬ. Критический анализ мирового опыта доклинической разработки ГТЛП для выявления ключевых проблем ДКИ и оптимизации дизайна исследований педиатрических орфанных ГТЛП для ускорения их перехода в клиническую практику.

ОБСУЖДЕНИЕ

ОБСУЖДЕНИЕ. Анализ литературных источников проводили в базах PubMed, Embase, Google Scholar, eLIBRARY.RU, cyberleninka.ru, а также на сайтах ведущих регуляторных органов за период 2020–2026 гг. В мире зарегистрировано около 20 ГТЛП, включая три препарата в Российской Федерации. Установлено, что дизайн ДКИ педиатрических орфанных ГТЛП базируется на принципе весомости доказательств и требует индивидуального подхода. Ключевыми элементами программы доклинической разработки являются исследования биораспределения вектора и трансгена, оценка экспрессии трансгена в целевых и нецелевых тканях, а также изучение выделения (шеддинга) вектора. Решающим фактором разработки выступает валидация модели на животных по клинически значимым конечным точкам. На примере препарата Элевидис для лечения мышечной дистрофии Дюшенна продемонстрирована важность оценки функциональных исходов (двигательная активность) и коррекции гистологических изменений (уменьшение некроза мышечной ткани), а на примере препарата Золгенсма для лечения спинальной мышечной атрофии — значимость снижения летальности как основной конечной точки. Выявлено, что оценка безопасности ГТЛП сопряжена с необходимостью анализа неопределенностей (долгосрочные риски, иммуногенность), которые регуляторные органы признают допустимыми в условиях отсутствия альтернативной терапии. Полученные данные подтверждают необходимость раннего взаимодействия разработчиков с регуляторными органами для оптимизации программ ДКИ.

ЗАКЛЮЧЕНИЕ

ЗАКЛЮЧЕНИЕ. Систематизированы особенности доклинической разработки педиатрических орфанных ГТЛП, ключевыми из которых являются гибкость дизайна на основе принципов весомости доказательств, проведение исследования биораспределения трансгена и самого вектора, приоритет функциональных конечных точек, тщательная валидация модели на животных и раннее взаимодействие с регуляторными органами. Практическая значимость работы заключается в обосновании подхода, позволяющего разработчикам оптимизировать программы ДКИ, а экспертам регуляторных органов — гармонизировать оценку эффективности и безопасности, что ускорит выход жизненно важных препаратов в клиническую практику для педиатрических пациентов с орфанными заболеваниями.

INTRODUCTION

INTRODUCTION. The lack of uniform regulatory requirements for preclinical studies (PCS) of pediatric orphan gene therapy medicinal products (GTMPs) complicates their development and marketing authorization. This review summarizes the key features of PCS for such products and analyzes the successful experience with two registered GTMPs to support approaches for accelerating the market entry of new products.

AIM

AIM. This study aimed to critically analyze global experience in the preclinical development of GTMPs to identify key challenges in PCS and to optimize the design of studies on pediatric orphan GTMPs for expediting their translation into clinical practice.

DISCUSSION

DISCUSSION. A literature search was conducted in PubMed, Embase, Google Scholar, eLIBRARY.RU, cyberleninka.ru, and on the websites of leading regulatory agencies for the period 2020–2026. Currently, about 20 GTMPs are registered worldwide, including three products in the Russian Federation. The design of PCS for pediatric orphan GTMPs was found to be based on the weight-of-evidence principle and requires an individualized approach. Key elements of the preclinical development program include biodistribution studies of the vector and transgene, assessment of transgene expression in target and non-target tissues, and evalu­ation of vector shedding. The critical success factor is validation of the animal model using clinically relevant endpoints. Using Elevidys (Duchenne muscular dystrophy) as an example, the importance of assessing functional outcomes (motor activity) and correcting histological changes (reduction of muscle tissue necrosis) was demonstrated, while Zolgensma (spinal muscular atrophy) illustrated the significance of mortality reduction as the primary endpoint. The safety assessment of GTMPs is associated with the need to analyze uncertainties (long-term risks, immunogenicity), which regulatory authorities consider acceptable in the absence of alternative therapy. The obtained data confirm the necessity of early engagement between developers and regulators to optimize PCS programs.

CONCLUSIONS

CONCLUSIONS. The performed analysis has systematized the specific features of preclinical development of pediatric orphan GTMPs, the key ones being flexibility of design based on weight-of-evidence principles, biodistribution studies of the transgene and the vector itself, prioritiza­tion of functional endpoints, thorough validation of the animal model, and early interaction with regulatory authorities. The practical significance of the work lies in substantiating an approach that enables developers to optimize PCS programs and helps regulatory experts harmonize the assessment of efficacy and safety, thereby accelerating the entry of life-saving medicinal products into clinical practice for pediatric patients with orphan diseases.

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