Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency
Open accessAbstract
Significance: Systemically administered lipid nanoparticles (LNPs) targeting the liver were able to express the cytoplasmic enzyme arginase 1 (ARG1) in a conditional knockout model of ARG1 deficiency. Metabolically, this resulted in maintaining normal plasma ammonia and arginine, preventing the build-up of excessive hepatic arginine, and obviated the development of guanidino compounds, a hallmark of this enzyme deficiency. Unlike controls, repeat dosing of LNPs encapsulating human codon-optimized ARG1 messenger RNA led to long-term survival without evidence of toxicity, restoration of ureagenesis, and the ability to handle toxic ammonia loading. These findings have implications for therapy of ARG1 deficiency, which is presently inadequately treated and leads to progressive neurological decline.
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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 [229]
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- Authors
- Truong, B., Allegri, G., Liu, X.-B., Burke, K. E., Zhu, X., Cederbaum, S. D., Häberle, J., Martini, P. G. V., & Lipshutz, G. S.
- Affiliations
- University of California, Los Angeles (US)
- University Children's Hospital Zurich (CH)
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095;
- Moderna, Inc., Cambridge, MA 02139;
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-09-09
- Volume
- 116
- Issue
- 42
- Pages
- 21150-21159
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6800360
- OpenAlex
- W2972630768
- Cited by
- 151
- References
- 48
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 29 · 2023: 28 · 2022: 25 · 2021: 18 · 2020: 13 · 2019: 1 · 2012: 1
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- HHS | National Institutes of Health (5 R01 NS100979)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- arginase deficiency, arginase-1, lipid nanoparticles, mRNA therapeutics, liver-targeted drug delivery, conditional knockout mouse model, urea synthesis, guanidino compounds, codon optimization, neurological deterioration
- MeSH terms
- Ammonia, Animals, Arginase, Arginine, Codon, Disease Models, Animal, Glutamine, Lipids, Liver, Liver Diseases, Male, Mice, Inbred C57BL, RNA, Messenger, Urea, Hyperargininemia, Hyperammonemia, Mice, Nanoparticles
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