Safety Evaluation of Lipid Nanoparticle–Formulated Modified mRNA in the Sprague-Dawley Rat and Cynomolgus Monkey
Abstract
The pharmacology, pharmacokinetics, and safety of modified mRNA formulated in lipid nanoparticles (LNPs) were evaluated after repeat intravenous infusion to rats and monkeys. In both species, modified mRNA encoding the protein for human erythropoietin (hEPO) had predictable and consistent pharmacologic and toxicologic effects. Pharmacokinetic analysis conducted following the first dose showed that measured hEPO levels were maximal at 6 hours after the end of intravenous infusion and in excess of 100-fold the anticipated efficacious exposure (17.6 ng/ml) at the highest dose tested. 24 hEPO was pharmacologically active in both the rat and the monkey, as indicated by a significant increase in red blood cell mass parameters. The primary safety-related findings were caused by the exaggerated pharmacology of hEPO and included increased hematopoiesis in the liver, spleen, and bone marrow (rats) and minimal hemorrhage in the heart (monkeys). Additional primary safety-related findings in the rat included mildly increased white blood cell counts, changes in the coagulation parameters at all doses, as well as liver injury and release of interferon γ–inducible protein 10 in high-dose groups only. In the monkey, as seen with the parenteral administration of cationic LNPs, splenic necrosis and lymphocyte depletion were observed, accompanied with mild and reversible complement activation. These findings defined a well-tolerated dose level above the anticipated efficacious dose. Overall, these combined studies indicate that LNP-formulated modified mRNA can be administered by intravenous infusion in 2 toxicologically relevant test species and generate supratherapeutic levels of protein (hEPO) in vivo.
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In vivo application of lipid nanoparticles has been reported to induce liver and lung injuries in rodents.
“In vivo application of lipid nanoparticles has been reported to induce liver and lung injuries in rodents170,173, which may be attributed to the cytotoxicity of the materials and the induction of”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
The complement system and Toll-like receptors may participate in innate immune activation by immunogenic lipids.
“Although the immunogenicity of these lipids has not yet been fully understood, complement system and Toll-like receptors may participate in innate immune activation170,173–175.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
Cationic and ionizable lipids have been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species.
“Cationic and ionizable lipids have also been reported to stimulate the secretion of pro-inflammatory cytokines and reactive oxygen species170–173.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [173]
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Background
- Authors
- Sedic, M., Senn, J. J., Lynn, A., Laska, M., Smith, M., Platz, S. J., Bolen, J., Hoge, S., Bulychev, A., Jacquinet, E., Bartlett, V., & Smith, P. F.
- Affiliations
- Moderna Therapeutics (United States) (US)
- AstraZeneca, Melbourn, Royston, UK
- PureTech (United States) (US)
- Akcea Therapeutics, Cambridge, MA
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Senn, Joseph J.
- Venue
- Veterinary Pathology
- Publisher
- SAGE Publications
- Published
- 2017-11-30
- Volume
- 55
- Issue
- 2
- Pages
- 341-354
- ISSN
- 0300-9858 (ISSN-L)
- 1544-2217
- OpenAlex
- W2774359469
- Semantic Scholar
- ff6e62a333b9a5177911689bb2e6b1d42baa1047
- Cited by
- 195
- References
- 29
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 29 · 2023: 36 · 2022: 36 · 2021: 23 · 2020: 13 · 2019: 10 · 2018: 6
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Veterinary Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Moderna
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- modified mRNA, human erythropoietin, intravenous infusion, hematopoiesis, splenic necrosis, lymphocyte depletion, complement activation, CXCL10, liver injury, coagulation parameters, nonclinical safety evaluation
- MeSH terms
- Animals, Blood Coagulation, Erythropoietin, Female, Hematopoiesis, Infusions, Intravenous, Leukocyte Count, Lipids, Macaca fascicularis, Male, RNA, Messenger, Rats, Sprague-Dawley, Rats, Nanoparticles
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