Increased erythropoiesis in mice injected with submicrogram quantities of pseudouridine-containing mRNA encoding erythropoietin
Open accessAbstract
Advances in the optimization of in vitro-transcribed mRNA are bringing mRNA-mediated therapy closer to reality. In cultured cells, we recently achieved high levels of translation with high-performance liquid chromatography (HPLC)-purified, in vitro-transcribed mRNAs containing the modified nucleoside pseudouridine. Importantly, pseudouridine rendered the mRNA non-immunogenic. Here, using erythropoietin (EPO)-encoding mRNA complexed with TransIT-mRNA, we evaluated this new generation of mRNA in vivo. A single injection of 100 ng (0.005 mg/kg) mRNA elevated serum EPO levels in mice significantly by 6 hours and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10-100-fold lower levels of EPO lasting only 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. As little as 10 ng mRNA doubled reticulocyte numbers. Weekly injection of 100 ng of EPO mRNA was sufficient to increase the hematocrit from 43 to 57%, which was maintained with continued treatment. Even when a large amount of pseudouridine-mRNA was injected, no inflammatory cytokines were detectable in plasma. Using macaques, we could also detect significantly-increased serum EPO levels following intraperitoneal injection of rhesus EPO mRNA. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications.
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Sequence-engineered, unmodified mRNA is competitive with nucleoside-modified mRNA with respect to protein yield in vivo.
“In summary, these data demonstrate that sequence-engineered, unmodified mRNA is competitive with nucleoside-modified mRNA with respect to protein yield in vivo.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [27]
The Results (page not provided) compare codon-optimized EPO mRNAs differing in whether they contain uridine or pseudouridine. In mice, the unmodified mRNA produced much lower EPO levels; 0.001 µg of pseudouridine-containing mRNA was as potent as 1 µg of unmodified mRNA in raising reticulocyte counts. This is contrary to the claimed comparable in-vivo yield. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredTwo 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 [27]
The Results (page unavailable) show that pseudouridine-modified EPO mRNA produced higher, longer-lasting EPO levels than uridine-containing EPO mRNA in mice. The Introduction mentions another study of modified mRNA for therapeutic proteins, but does not establish that it independently compared modified and unmodified EPO mRNA. This source therefore supports the superiority finding for one study, not the claim about two independent EPO studies. (LLM, conf=0.84)
Experimental — accuracy not yet measuredConclusive 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 Kariko et al, 2012
Short-lived proteins can significantly profit by being expressed from mRNA (Kariko et al, 2012; Thess et al, 2015).
“By contrast, short‐lived proteins can significantly profit by being expressed from mRNA (Kariko et al, 2012; Thess et al, 2015).”
From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Kariko et al, 2012
The physiological effect of administering engineered Epo mRNA is as strong as that observed with pseudouridine-modified mRNA.
“Taking into account the lower reticulocyte numbers obtained with 100 U of recombinant EPO protein as well as the lower background levels compared to a recent publication,27 the physiological effect of administering our engineered Epo mRNA is as strong as that observed with pseudouridine-modified mRNA.”
From Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals (2015) · cites this paper as [27]
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 [27]
At present, the 3′ UTR is mainly derived from hemoglobin subunit α (HBA) and subunit β (HBB) genes, but it can also be derived from albumin (ALB), heat-shock protein 70 (Hsp70), tyrosine hydroxylase (TH), and collagen alpha 1 (COL1A1) genes.
“At present, the 3′ UTR is mainly derived from hemoglobin subunit α (HBA) and subunit β (HBB) genes,140 but it can also be derived from albumin (ALB), heat-shock protein 70 (Hsp70), tyrosine hydroxylase (TH), and collagen alpha 1 (COL1A1) genes.141–143”
From Advances in COVID-19 mRNA vaccine development (2022) · cites this paper as [142]
Incorporation of modified nucleosides into mRNA can significantly improve biological stability and translational capacity while decreasing the innate immune response.
“However, the incorporation of modified nucleosides into mRNA can significantly improve the biological stability and translational capacity of the mRNA while decreasing the innate immune response.36, 37, 38”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [38]
All U nucleotides in the mRNA vaccines have been modified to N1-methyl-pseudouridine (Ψ) to reduce immune reaction towards mRNA and to increase protein production.
“However, all U nucleotides in the mRNA vaccines have been modified to N1-methyl-pseudouridine (Ψ) [14] to reduce immune reaction towards mRNA and to increase protein production [2,13,58].”
From Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines (2021) · cites this paper as [58]
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- Authors
- Karikó, K., Muramatsu, H., Keller, J. M., & Weissman, D.
- Affiliations
- University of Pennsylvania (US)
- National Institutes of Health (US)
- Corresponding author
- Karikó, Katalin
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2012-05
- Volume
- 20
- Issue
- 5
- Pages
- 948-953
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3345990
- OpenAlex
- W2054412308
- Cited by
- 282
- References
- 34
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 22 · 2023: 27 · 2022: 35 · 2021: 30 · 2020: 17 · 2019: 14 · 2018: 16 · 2017: 17 · 2016: 25 · 2015: 24 · 2014: 11 · 2013: 13 · 2012: 6
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R42HL087688, R42HL87688)
- National Institute of Allergy and Infectious Diseases (R01 AI50484, R01AI050484)
- National Institute of Neurological Disorders and Stroke (R01NS029331)
- National Institute of Dental and Craniofacial Research (R21DE019059)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- erythropoietin, in vitro transcribed mRNA, erythropoiesis, immunogenicity, reticulocyte count, hematocrit, rhesus monkeys, therapeutic protein delivery
- MeSH terms
- Animals, Cell Count, Chromatography, High Pressure Liquid, Erythropoiesis, Erythropoietin, Female, Genetic Vectors, Hematocrit, Humans, Injections, Intraperitoneal, Macaca mulatta, Mice, Inbred BALB C, Pseudouridine, Reticulocytes, RNA, Messenger, Drug Delivery Systems, Cell Proliferation, Mice
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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