Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immature dendritic cells and induce superior immune responses in vivo
Open accessAbstract
Vaccination with in vitro transcribed RNA coding for tumor antigens is considered a promising approach for cancer immunotherapy and has already entered human clinical testing. One of the basic objectives for development of RNA as a drug is the optimization of immunobioavailability of the encoded antigen in vivo. By analyzing the effect of different synthetic 5' mRNA cap analogs on the kinetics of the encoded protein, we found that m(2)(7,2'-O)Gpp(S)pG (beta-S-ARCA) phosphorothioate caps, in particular the D1 diastereoisomer, profoundly enhance RNA stability and translational efficiency in immature but not mature dendritic cells. Moreover, in vivo delivery of the antigen as beta-S-ARCA(D1)-capped RNA species is superior for protein expression and for efficient priming and expansion of naïve antigen-specific T cells in mice. Our findings establish 5' mRNA cap analogs as yet another module for tuning immunopharmacological properties of recombinant antigen-encoding RNA for vaccination purposes.
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Previous strategies to increase mRNA stability have yielded modest improvements in RNA stability.
“These strategies have yielded modest improvements in RNA stability10, 13–16, and thus alternative approaches to RNA stabilization, such as circularization, are desirable.”
From Engineering circular RNA for potent and stable translation in eukaryotic cells (2018) · cites this paper as [14]
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- Authors
- Kuhn, A. N., Diken, M., Kreiter, S., Selmi, A., Kowalska, J., Jemielity, J., Darzynkiewicz, E., Huber, C., Türeci, Ö., & Sahin, U.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- University of Warsaw (PL)
- Venue
- Gene Therapy
- Published
- 2010-04-22
- Volume
- 17
- Issue
- 8
- Pages
- 961-971
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- OpenAlex
- W2085865810
- Cited by
- 226
- References
- 32
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 19 · 2023: 21 · 2022: 13 · 2021: 20 · 2020: 15 · 2019: 9 · 2018: 16 · 2017: 11 · 2016: 17 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 7
- FWCI
- 4.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (55005604)
- Bundesministerium für Bildung und Forschung
- Ministerstwo Edukacji i Nauki
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- mRNA vaccines, RNA stability, translation efficiency, immature dendritic cells, cancer immunotherapy, in vitro transcribed mRNA, immunopharmacology
- MeSH terms
- Dendritic Cells, Half-Life, Humans, Luciferases, RNA, RNA Cap Analogs, Protein Biosynthesis, Vaccines, Synthetic, Genes, Reporter, Antigen Presentation, Cancer Vaccines, RNA Stability, Phosphorothioate Oligonucleotides
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