Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening
Open accessAbstract
Synthetic mRNA has emerged as a powerful tool for the transfer of genetic information, and it is being explored for a variety of therapeutic applications. Many of these applications require prolonged intracellular persistence of mRNA to improve bioavailability of the encoded protein. mRNA molecules are intrinsically unstable and their intracellular kinetics depend on the UTRs embracing the coding sequence, in particular the 3' UTR elements. We describe here a novel and generally applicable cell-based selection process for the identification of 3' UTRs that augment the expression of proteins encoded by synthetic mRNA. Moreover, we show, for two applications of mRNA therapeutics, namely, (1) the delivery of vaccine antigens in order to mount T cell immune responses and (2) the introduction of reprogramming factors into differentiated cells in order to induce pluripotency, that mRNAs tagged with the 3' UTR elements discovered in this study outperform those with commonly used 3' UTRs. This approach further leverages the utility of mRNA as a gene therapy drug format.
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Both BNT162b1 and BNT162b2 are pharmacologically optimized N1-methylpseudouridine nucleoside-modified mRNAs given intramuscularly in a prime-boost regimen.
“Both of the candidates are pharmacologically optimized 15,16 , N 1 -methylpseudouridine nucleoside-modified mRNAs 17 that are administered intramuscularly in a prime-boost regimen 21”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [16]
The antigen-encoding RNA contains sequence elements that increase RNA stability and translation efficiency in human dendritic cells.
“The antigen-encoding RNA contains sequence elements that increase RNA stability and translation efficiency in human dendritic cells 15,16 .”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [16]
Specific UTRs, such as one or two copies of the 3′ UTR of globin or a short 14-nucleotide 5′ UTR, increase the translational efficiency of mRNAs.
“numerous works have developed specific UTRs to increase the translational efficiency of mRNAs, as the use of one or two copies of the 3′ UTR of the globin or other known stable mRNA8,9 or short 14-nucleotide 5′ UTR.27”
From Combining an optimized mRNA template with a double purification process allows strong expression of in vitro transcribed mRNA (2021) · cites this paper as [8]
Orlandini von Niessen et al. showed that 3′UTRs containing mtRNR1 and AES promote the expression of the upstream gene.
“They showed that 3′UTRs containing mtRNR1 and AES promote the expression of the upstream gene.”
From Untranslated Region Sequences and the Efficacy of mRNA Vaccines against Tuberculosis (2024) · cites this paper as [17]
The structural characteristics of mRNA such as the CAP, poly(A) tail, and UTRs directly impact mRNA stability and translation efficiency.
“The structural characteristics of mRNA such as the CAP, poly(A) tail, and untranslated regions (UTRs) directly impact mRNA stability and translation efficiency (Orlandini von Niessen et al. 2019; Holtkamp et al. 2006).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Orlandini von Niessen et al. 2019
BNT162b2 uses 5′ UTR human β-globin RNA with optimized Kozak sequence, 3′ UTR AES and mtRNR1 3′ UTR motives, and 110 Poly(A) tail with nucleotide-linker (GCAUAUGACU).
“In addition, 5′ UTR: human -globin RNA with optimized Kozak sequence, 3′ UTR: AES and mtRNR1 3′ UTR Motives, and 110 Poly(A) tail with nucleotide-linker (GCAUAUGACU) are also used (Orlandini von Niessen et al. 2019).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Orlandini von Niessen et al. 2019
mtRNR1, AES, and EMCV individually have previously been found to influence mRNA stability.
“As 3′UTRs, various combinations of mtRNR1, AES, and EMCV were chosen, which individually have previously also been found to influence mRNA stability [34,39].”
From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [34]
The number of studies assessing the contribution of certain UTRs to the expression of heterologous RNAs is rather small.
“Of note, despite active research into the properties of UTRs, the number of studies assessing the contribution of certain UTRs to the expression of heterologous RNAs is rather small [34,35].”
From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [34]
3′UTRs containing mtRNR1 and AES in any order promote overexpression of an upstream gene.
“Orlandini von Niessen and coworkers [34] have shown that 3′UTRs containing mtRNR1 and AES in any order promote overexpression of an upstream gene.”
From Effects of Combinations of Untranslated-Region Sequences on Translation of mRNA (2023) · cites this paper as [34]
BioNTech/Pfizer's modRNA platform RNA sequence used for BNT162b2 consists of human α-globin 5′ untranslated region (UTR), amino-terminal enhancer of split (AES), and mtRNR1 3′ UTR motifs and a poly(A) tail consisting of A30LA70.
“BioNTech/Pfizer's modRNA platform RNA sequence (used for BNT162b2) consists of human α-globin 5′ untranslated region (UTR), amino-terminal enhancer of split (AES), and mtRNR1 3′ UTR motifs91 and a poly(A) tail consisting of A30LA70 (linker [L]: GCAUAUGACU),81”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [91]
BNT162b2 and mRNA-1273 are composed of 1-methylpseudouridine-modified full-length spike mRNA, with proline substitutions, that is GC rich, codon optimized, and composed of standard mRNA components: cap, 5′ UTR, coding sequence, 3′ UTR, and a poly(A) tail.
“BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) are composed of 1-methylpseudouridine-modified full-length spike mRNA, with proline substitutions, that is GC rich, codon optimized, and composed of standard mRNA components: cap, 5′ UTR, coding sequence, 3′ UTR, and a poly(A) tail.”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [91]
UTR performance can vary by cell type, so alternative UTR sequences optimized for the desired application and intended cell target may be used.
“However, because UTR performance can vary by cell type, alternative UTR sequences may be used that have been optimized for the desired application and intended cell target16–18.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [17]
The design of non-coding structural elements of mRNA such as the CAP structure, poly(A) tail and untranslated regions has a major impact on mRNA stability and translation capacity.
“The design of (non-coding) structural elements of the mRNA such as the CAP structure, poly(A) tail and untranslated regions (UTRs) all have a major impact on the mRNA stability and translation capacity [31,32]”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [31]
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- Authors
- Orlandini von Niessen, A. G., Poleganov, M. A., Rechner, C., Plaschke, A., Kranz, L. M., Fesser, S., Diken, M., Löwer, M., Vallazza, B., Beissert, T., Bukur, V., Kuhn, A. N., Türeci, Ö., & Sahin, U.
- Affiliations
- BioNTech (Germany) (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 27
- Issue
- 4
- Pages
- 824-836
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6453560
- OpenAlex
- W2903777694
- Cited by
- 365
- References
- 60
- Citations by year
- 2026: 51 · 2025: 66 · 2024: 68 · 2023: 52 · 2022: 55 · 2021: 45 · 2020: 21 · 2019: 7
- FWCI
- 6.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- synthetic mRNA, mRNA therapeutics, 3' untranslated region, mRNA stability, T cell response, reprogramming factors, induced pluripotency, gene therapy
- MeSH terms
- Animals, Blood Donors, Cells, Cultured, Female, Fibroblasts, Half-Life, Humans, Mice, Inbred BALB C, RNA, Messenger, Vaccination, Genetic Therapy, Gene Library, Gene Transfer Techniques, Cancer Vaccines, 3' Untranslated Regions, RNA Stability, Mice, Induced Pluripotent Stem Cells, Cellular Reprogramming
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