Preclinical development of pediatric orphan gene therapy medicinal products: Analysis of approaches and challenges (review)

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. 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. 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. 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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