mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency
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Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.
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The therapeutic potential of mRNA-based protein replacement therapies has been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I, acute intermittent porphyria, Fabry disease, Crigler-Najjar syndrome type 1, α1 antitrypsin deficiency, methylmalonic acidaemia/aciduria, arginase deficiency, citrin deficiency and glycogen storage disease type I.
“The therapeutic potential of mRNA-based protein replacement therapies has also been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225, Crigler–Najjar syndrome type 1 (ref.226), α1 antitrypsin deficiency227, methylmalonic acidaemia/aciduria228, arginase deficiency229, citrin defic”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [230]
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- Authors
- Cao, J., An, D., Galduroz, M., Zhuo, J., Liang, S., Eybye, M., Frassetto, A., Kuroda, E., Funahashi, A., Santana, J., Mihai, C., Benenato, K. E., Kumarasinghe, E. S., Sabnis, S., Salerno, T., Coughlan, K., Miracco, E. J., Levy, B., Besin, G., Schultz, J., Lukacs, C., Guey, L., Finn, P., Furukawa, T., Giangrande, P. H., Saheki, T., & Martini, P. G. V.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Kagoshima University (JP)
- Corresponding author
- Martini, Paolo G.V.
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 27
- Issue
- 7
- Pages
- 1242-1251
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6612659
- OpenAlex
- W2940535024
- Cited by
- 70
- References
- 47
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 14 · 2021: 9 · 2020: 6 · 2019: 4
- FWCI
- 2.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Moderna
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- citrin deficiency, SLC25A13, mRNA therapeutics, lipid nanoparticles, blood ammonia, mouse model
- MeSH terms
- Loss of Function Mutation, Animals, Behavior, Animal, Disease Models, Animal, Glucosephosphate Dehydrogenase, HeLa Cells, Humans, Lipids, Mice, Inbred C57BL, Mitochondria, RNA, Messenger, Transfection, Genetic Therapy, Open Reading Frames, Drug Delivery Systems, Treatment Outcome, Mice, Knockout, Citrullinemia, Mitochondrial Membrane Transport Proteins, Mice, Nanoparticles, Gene Knockout Techniques, Hep G2 Cells
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