Design Features of Nonclinical Studies for In Vivo Gene Therapy Medicinal Products. Part 2: Pharmacokinetic and Toxicological Studies
https://doi.org/10.35401/2541-9897-2026-11-1-148-156
Abstract
The article focuses on the specific design features of nonclinical studies (NCS) of in vivo gene therapy medicinal products which involve the administration of vectors with recombinant nucleic acids into the patient’s body for the correction of genetic disorders and treatment of oncological diseases. This work highlights the key aspects of conducting pharmacokinetic and toxicological studies, identified through the analysis of expert reports from global gene therapy medicinal products manufacturers. These aspects include dose selection and route of administration; identification of specific studies applicable to all in vivo gene therapy medicinal products and the justification of study lists for products using different types of vectors; as well as duration of studies and the selection of appropriate models to demonstrate product safety and to detect potential adverse effects associated with their use.
Keywords
gene therapy products,
nonclinical studies,
pharmacokinetic studies,
toxicological studies,
vector,
transgene
Supporting agencies: The study was carried out within the framework of FSBI “SCEEMP” No. № 056-00001-25-01 for applied scientific research (Research State Registration Number No. 124022200093-9).
About the Authors
O. A. Rachinskaya
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation
Russian Federation
Olga A. Rachinskaya - Cand. Sci. (Biol.), Leading Expert, Laboratory of Biomedical Cell Products, Scientific Centre for Expert Evaluation of Medicinal Products.
Petrovskii bulvar 8/2, Moscow, 127051
E. V. Melnikova
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation
Russian Federation
Ekaterina V. Melnikova - Cand. Sci. (Biol.), Head of the Laboratory of Biomedical Cell Products, Scientific Centre for Expert Evaluation of Medicinal Products.
Moscow
V. A. Merkulov
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation
Russian Federation
Vadim A. Merkulov - Dr. Sci. (Med.), Professor, Deputy General Director, Scientific Centre for Expert Evaluation of Medicinal Products.
Moscow
References
1. European Medicines Agency. Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products. European Medicines Agency; 2018. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-clinical-and-clinical-aspects-gene-therapy-medicinal-products_en.pdf
2. Rachinskaya O.A., Melnikova E.V., Merkulov V.A. Design Features of Nonclinical Studies of In Vivo Gene Therapy Medicinal Products. Part 1: Pharmacological studies. Innovative Medicine of Kuban. 2025;10(4):113-120. https://doi.org/10.35401/2541-9897-2025-10-4-113-120
3. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Guideline: Nonclinical Biodistribution Considerations for Gene Therapy Products S12. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2023. Accessed April 13, 2025. https://database.ich.org/sites/default/files/ICH_S12_Step4_Guideline_2023_0314.pdf
4. Moffit JS, Blanset DL, Lynch JL, et al. Regulatory consideration for the nonclinical safety assessment of gene therapies. Hum Gene Ther. 2022;33(21–22):1126–1141. PMID: 35994386. PMCID: PMC9700330. https://doi.org/10.1089/hum.2022.090
5. European Medicines Agency. ICH Considerations: General Principles to Address Virus and Vector Shedding. European Medicines Agency; 2009. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-considerations-general-principles-address-virus-and-vector-shedding_en.pdf
6. European Medicines Agency. Assessment Report: Zolgensma. International Non-Proprietary Name: Onasemnogene abeparvovec. Procedure No. EMEA/H/C/004750/0000. European Medicines Agency; 2020. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/zolgensma-epar-public-assessment-report_en.pdf
7. European Medicines Agency. Assessment Report: Luxturna. International Non-Proprietary Name: Voretigene neparvovec. Procedure No. EMEA/H/C/004451/0000. European Medicines Agency; 2019. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/luxturna-epar-public-assessment-report_en.pdf
8. European Medicines Agency. Assessment Report: Upstaza. International Non-Proprietary Name: Eladocagene exuparvovec. Procedure No. EMEA/H/C/005352/0000. European Medicines Agency; 2022. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/upstaza-epar-public-assessment-report_en.pdf
9. European Medicines Agency. Assessment Report: Roctavian. International Non-Proprietary Name: Valoctocogene roxaparvovec. Procedure No. EMEA/H/C/005830/0000. European Medicines Agency; 2022. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/roctavian-epar-public-assessment-report_en.pdf
10. European Medicines Agency. Assessment Report: Glybera. International Nonproprietary Name: Alipogene tiparvovec. Procedure No. EMEA/H/C/002145. European Medicines Agency; 2012. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/glybera-epar-public-assessment-report_en.pdf
11. Summary Basis for Regulatory Action - HEMGENIX. FDA; 2022. Accessed April 13, 2025. https://www.fda.gov/media/164094/download?attachment
12. Summary Basis for Regulatory Action – ELEVIDYS. FDA; 2023. Accessed April 13, 2025. https://www.fda.gov/media/169746/download?attachment
13. Summary Basis for Regulatory Action. FDA; 2015. Accessed April 13, 2025. https://wayback.archive-it.org/7993/20190425013447/ https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM473103.pdf
14. Melnikova EV, Rachinskaya OA, Merkulov VA. Advanced therapy medicines based on oncolytic viruses (part I: development and authorisation of products in China). The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2021;11(3):148-159. (In Russ.). https://doi.org/10.30895/1991-2919-2021-11-148-159
15. Коллегия Евразийской экономической комиссии. Решение от 26 ноября 2019 г. № 202 «Об утверждении Руководства по доклиническим исследованиям безопасности в целях проведения клинических исследований и регистрации лекарственных препаратов». Коллегия Евразийской экономической комиссии; 2019. Дата обращения: 13.04.2025. https://docs.eaeunion.org/upload/iblock/072/nzmd6i2fwbj90ndkm4riswwcz9ecgsa2/clcd_29112019_202_doc.pdf
16. European Medicines Agency. Assessment Report: Durveqtix. International non-proprietary name: Fidanacogene elaparvovec. Procedure No. EMEA/H/C/004774/0000. European Medicines Agency; 2024. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/durveqtix-epar-public-assessment-report_en.pdf
17. Summary Basis for Regulatory Action – ADSTILADRIN. FDA; 2022. Accessed April 13, 2025. https://www.fda.gov/media/164532/download?attachment
18. Tsai HY, Hamilton A, Tinch E, et al. Genome wide association and genomic prediction for growth traits in juvenile farmed Atlantic salmon using a high density SNP array. BMC Genomics. 2015;16:969. PMID: 26582102. PMCID: PMC4652364. https://doi.org/10.1186/s12864-015-2117-9
19. Astapova OV, Berchatova AA. Gene therapy medicinal products: non-clinical safety studies. Safety and Risk of Pharmacotherapy. 2023;11(1):73–96. (In Russ.). https://doi.org/10.30895/2312-7821-2023-11-1-329
20. Donsante A, Miller DG, Li Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma. Science. 2007;317(5837):477. PMID: 17656716. https://doi.org/10.1126/science.1142658
21. Dalwadi DA, Torrens L, Abril-Fornaguera J, et al. Liver injury increases the incidence of HCC following AAV gene therapy in mice. Mol Ther. 2021;29(2):680–690. PMID: 33554867. PMCID: PMC7854305. https://doi.org/10.1016/j.ymthe.2020.10.018
22. Chandler RJ, LaFave MC, Varshney GK, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy. J Clin Invest. 2015;125(2):870–880. PMID: 25607839. PMCID: PMC4319425. https://doi.org/10.1172/JCI79213
23. Nguyen GN, Everett JK, Kafle S, et al. A long-term study of AAV gene therapy in dogs with hemophilia A identifies clonal expansions of transduced liver cells. Nat Biotechnol. 2021;39(1):47–55. PMID: 33199875. PMCID: PMC7855056. https://doi.org/10.1038/s41587-020-0741-7
24. Delytact Injection_Daiichi Sankyo Company, Limited_Review Report. PMDA; 2021. Accessed April 13, 2025. https://www.pmda.go.jp/files/000242808.pdf
25. Couto L, Parker A, Gordon JW. Direct exposure of mouse spermatozoa to very high concentrations of a serotype-2 adeno-associated virus gene therapy vector fails to lead to germ cell transduction. Hum Gene Ther. 2004;15(3):287–291. PMID: 15018737. https://doi.org/10.1089/104303404322886138
26. Arruda VR, Fields PA, Milner R, et al. Lack of germline transmission of vector sequences following systemic administration of recombinant AAV-2 vector in males. Mol Ther. 2001;4(6):586–592. PMID: 11735343. https://doi.org/10.1006/mthe.2001.0491
27. Roehl HH, Leibbrandt ME, Greengard JS, et al. Analysis of testes and semen from rabbits treated by intravenous injection with a retroviral vector encoding the human factor VIII gene: no evidence of germ line transduction. Hum Gene Ther. 2000;11(18):2529–2540. PMID: 11119423. https://doi.org/10.1089/10430340050208000
28. European Medicines Agency. Assessment Report: Imlygic. International Non-Proprietary Name: Talimogene laherparepvec. Procedure No. EMEA/H/C/002771/0000European Medicines Agency; 2019. Accessed April 13, 2025. https://www.ema.europa.eu/en/documents/assessment-report/imlygic-epar-public-assessment-report_en.pdf
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For citations:
Rachinskaya O.A., Melnikova E.V., Merkulov V.A. Design Features of Nonclinical Studies for In Vivo Gene Therapy Medicinal Products. Part 2: Pharmacokinetic and Toxicological Studies. Innovative Medicine of Kuban. 2026;11(1):148-156. (In Russ.) https://doi.org/10.35401/2541-9897-2026-11-1-148-156
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