REVIEW: Selection of UTRs in mRNA-Based Gene Therapy and Vaccines

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Ilya A. Volkhin^1#, Anastasia Iu. Paremskaia^2,3#, Maria A. Dashian³, Darya S. Smeshnova², Roman E. Pavlov², Olga N. Mityaeva^2,4, Pavel Yu. Volchkov^2,5, and Andrei A. Deviatkin^2,6,7,a*

¹Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

²Federal Research Center for Innovator and Emerging Biomedical and Pharmaceutical Technologies, 125315 Moscow, Russia

³Department of Biomedicine, Pirogov Medical University, 117997 Moscow, Russia

⁴Moscow Center for Advanced Studies, 123592 Moscow, Russia

⁵Center for Personalized Medicine, Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia

⁶Laboratory of Postgenomic Technologies, Izmerov Research Institute of Occupational Health, 105275 Moscow, Russia

⁷Federal State Budgetary Institution ‘Centre for Strategic Planning and Management of Biomedical Health Risks’ of the Federal Medical and Biological Agency, 119121 Moscow, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to the work.

Received: December 25, 2024; Revised: May 19, 2025; Accepted: May 28, 2025

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The untranslated regions (UTRs) of messenger RNAs (mRNAs) play a crucial role in regulating translational efficiency, stability, and tissue-specific expression. The review describes various applications and challenges of UTR design in the development of gene therapy and mRNA-based therapeutics. UTRs affect critical biological functions, such as mRNA stability, modulation of protein synthesis, and attenuation of immune response. Incorporating tissue-specific microRNA (miRNA)-binding sites into 3′ UTRs might improve precise targeting of transgene expression and minimize off-target effects. Nucleotide modifications (pseudouridine, N1-methyladenosine, and N4-acetylcytidine) in mRNA and UTRs in particular, improve mRNA stability and translational efficiency. At the same time, several challenges remain, such as lack of consensus on UTRs best suited for certain biomedical applications. Current efforts are focused on integrating high-throughput screening, computational modeling, and experimental validation to refine UTR-based therapeutic strategies. The review presents current information on the design of UTRs and their role in therapeutic applications, with special focus on the possibilities and limitations of existing approaches.

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KEY WORDS: gene therapy, mRNA vaccine, UTR, rational design, optimization, RNA secondary structure

DOI: 10.1134/S0006297924604659

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