The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“In another study by Kormann and colleagues, translation was maximized and innate immune response was reduced in a mouse lung disease model by introducing chemically-modified nucleotides during in vitro transcription of mRNA (IVT-mRNA), coding for surfactant protein B (SP-B) with a 25% replacement of cytidine and uridine by modified 5-methyl cytidine (5-methyl CTP) and 2-thio uridine (2-thio UTP),”
From Human cellular CYBA UTR sequences increase mRNA translation without affecting the half-life of recombinant RNA transcripts (2016) · cites this paper as [19]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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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