Designing 5′ UTR sequences improves the capacity of mRNA therapeutics in preclinical models of aging and obesity

🥈 Top 2% JournalJan 4, 2026Molecular therapy : the journal of the American Society of Gene Therapy

Changing mRNA starting sequences improves mRNA medicine effectiveness in early tests on aging and obesity

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Abstract

The 5' UTR of RPS9 enhances protein output in synthetic mRNAs, particularly in aged and obese mouse models.

Sequences in the 5' UTR of certain ribosomal protein mRNAs can significantly improve the therapeutic potential of mRNA.
Bioinformatic analysis shows that ribosomal protein mRNAs are prevalent but are regulated differently by specific proteins.
Among 11 ribosomal protein mRNAs studied, RPL18, RPL35, and RPS9 are identified as enhancing protein production in human and mouse cells.
Mutations in the 5' UTR indicate that the improvement in protein output does not depend on the terminal oligopyrimidine motif.
In aged mice and those on a high-fat diet, synthetic mRNAs using RPS9's 5' UTR show better protein expression and greater immune response.

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The utility of messenger RNA (mRNA) as a therapeutic modality has been widely demonstrated with the containment of COVID-19, yet the decisions in sequence design in the untranslated regions (UTR) remain largely unexplored, especially in preclinical models. Here, we focus on the 5' UTR of mRNA and discover sequences that improve therapeutic potential in mouse models of aging and obesity. Bioinformatic analysis of RNA-seq, scRNA-seq, Ribo-seq, and CLIP-seq data revealed that ribosomal protein (RP) mRNAs are abundant and ubiquitous but undergo distinct translational regulation by LARP1 and LARP4. Of 11 RP mRNAs, we find that the 5' UTR of RPL18, RPL35 and RPS9 improves the protein output of synthetic mRNAs in human and mouse cells. Investigation of mutant 5' UTRs indicate that this improvement is independent of its terminal oligopyrimidine (TOP) motif but strong in cells with high levels of reactive oxygen species (ROS). In aged mice and mice under high-fat diet, synthetic mRNAs with RPS9's 5' UTR resulted in improved protein expression and enhanced humoral immunity through Th2 cytokines when encoding viral antigens. Altogether, our results highlight the importance of UTR sequence in expanding the therapeutic potential of synthetic mRNAs for aged individuals and those diagnosed with obesity.

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