Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
Abstract
Current viral vectors for gene therapy are associated with serious safety concerns, including leukemogenesis, and nonviral vectors are limited by low gene transfer efficiency. Here we investigate the therapeutic utility of chemically modified mRNA as an alternative to DNA-based gene therapy. A combination of nucleotide modifications abrogates mRNA interaction with Toll-like receptor (TLR)3, TLR7, TLR8 and retinoid-inducible gene I (RIG-I), resulting in low immunogenicity and higher stability in mice. A single intramuscular injection of modified murine erythropoietin mRNA raises the average hematocrit in mice from 51.5% to 64.2% after 28 days. In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP-B expression, and treated mice survived until the predetermined end of the study after 28 days.
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Substitution of chemically modified nucleotides in mRNA enhances stability and transfection capability and decreases immunogenicity.
“Substitution of chemically modified nucleotides in messenger ribonucleic acid (mRNA) enhances stability and transfection capability, and decreases immunogenicity1–3”
From Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency (2025) · cites this paper as [2]
Conclusive data have also been presented for mRNA as a platform for protein (replacement) therapies.
“Conclusive data have also been presented for mRNA as a platform for protein (replacement) therapies (Kormann et al, 2011; Kariko et al, 2012; Zangi et al, 2013; Thess et al, 2015; Balmayor et al, 2016).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Kormann et al, 2011
Unmodified Epo mRNA was immunostimulatory and failed to induce sufficient protein expression in mice, whereas nucleoside-modified mRNA achieved detectable protein expression and physiological effects.
“Whereas unmodified Epo mRNA was immunostimulatory and failed to induce sufficient protein expression in mice, a few micrograms of nucleoside-modified mRNA were enough to achieve detectable protein expression and physiological effects upon direct administration to murine muscle.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [26]
Conventional unmodified mRNAs are inferior to molecules harboring specific nucleoside modifications, but the picture changes dramatically with sophisticated sequence-engineering.
“Our work principally confirms that conventional unmodified mRNAs are inferior to molecules harboring specific nucleoside modifications as suggested by various recent reports,23,24,25,26,27 however, the picture changes dramatically with a sophisticated sequence-engineering.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [26]
Two independent studies found superiority of nucleoside-modified compared to unmodified Epo mRNA.
“Two independent studies on erythropoietin-encoding mRNA found a superiority of nucleoside-modified compared to unmodified mRNA.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [26]
Local administrations may be possible without the need for an mRNA delivery system.
“While local administrations may be possible without the need for an mRNA delivery system,26,42”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [26]
Injection of nucleoside-modified mRNA containing 25% thio-uridine and 25% 5-methylcytidine resulted in Epo levels five times greater than untreated animals 2 weeks after injection.
“Kormann et al., demonstrated that 2 weeks following injection of nucleoside-modified mRNA containing 25% thio-uridine and 25% 5-methylcytidine resulted in Epo levels five times greater than that in untreated animals.”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Kormann et al. 2011
Unmodified mRNA showed no significant alterations and merely elicited a considerable immunological response.
“Unmodified mRNA, on the other hand, showed no significant alterations and merely elicited a considerable immunological response (Kormann et al. 2011).”
From Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency (2022) · cites this paper as Kormann et al. 2011
Chemical modifications of nucleic acid bases, sugar rings, and ends are resistant to nuclease degradation, reduce immunogenicity, and improve interaction with target cells.
“Therefore, chemists have creatively modified nucleic acid bases, sugar rings, 3 ‘and 5’ ends. These modifications are resistant to nuclease degradation, reduce immunogenicity and improve the interaction with target cells.311”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [311]
When poly(A) tail size increases to 120 bp, the expression level of the corresponding protein increases accordingly; however, when poly(A) tail size is greater than 120 bp, the expression level of the corresponding protein did not increase.
“Studies have shown that when poly(A) tail size increases to 120 bp, the expression level of the corresponding protein increases accordingly. However, when poly(A) tail size is greater than 120 bp, the expression level of the corresponding protein did not increase.152”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [152]
Kormann and colleagues replaced 25% of mRNA cytosine with m5C and 25% of uridine with s2U, which improved mRNA stability and increased protein translation in mice.
“Kormann and colleagues152 replaced 25% of mRNA cytosine with m5C and 25% of uridine with s2U, which improved mRNA stability and increased protein translation in mice.”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [152]
Unmodified mRNA evoked substantial immune activation but produced no significant changes in Epo levels.
“In contrast, no significant changes were detected with unmodified mRNA, which only evoked a substantial immune activation [44].”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [44]
Kormann et al. demonstrated that nucleoside-modified mRNA encoding erythropoietin, with 25% thio-uridine and 25% 5-methylcytidine incorporated, resulted in five times higher Epo levels compared to untreated mice two weeks after intramuscular administration.
“In a therapeutic setting, Kormann et al., demonstrated that nucleoside-modified mRNA encoding erythropoietin (Epo), in which 25% thio-uridine and 25% 5-methylcytidine was incorporated, resulted in five times higher Epo levels compared to untreated mice, two weeks after i.m. administration.”
From Three decades of messenger RNA vaccine development (2019) · cites this paper as [44]
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- Authors
- Kormann, M. S. D., Hasenpusch, G., Aneja, M. K., Nica, G., Flemmer, A. W., Herber-Jonat, S., Huppmann, M., Mays, L. E., Illenyi, M., Schams, A., Griese, M., Bittmann, I., Handgretinger, R., Hartl, D., Rosenecker, J., & Rudolph, C.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- University Children's Hospital Tübingen (DE)
- Agaplesion Diakonieklinikum Rotenburg (DE)
- Corresponding author
- Kormann, Michael S D
- Rudolph, Carsten
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2011-01-09
- Volume
- 29
- Issue
- 2
- Pages
- 154-157
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2071302752
- Cited by
- 733
- References
- 27
- Citations by year
- 2026: 26 · 2025: 41 · 2024: 59 · 2023: 54 · 2022: 64 · 2021: 61 · 2020: 69 · 2019: 53 · 2018: 56 · 2017: 58 · 2016: 65 · 2015: 48 · 2014: 23 · 2013: 28 · 2012: 17
- FWCI
- 10.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- 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 and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- chemically modified mRNA, mRNA therapeutics, erythropoietin, surfactant protein B, immunogenicity, Toll-like receptors, RIG-I, intramuscular injection, hematocrit, non-viral gene therapy, lung disease
- MeSH terms
- Animals, Erythropoietin, Histocytochemistry, Lung, Mice, Transgenic, Proteolipids, RNA, Messenger, Gene Transfer Techniques, RNA Stability, Mice, Kaplan-Meier Estimate
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