Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency
Open accessAbstract
We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.
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Supplement of desired enzymes by lipid nanoparticle-mRNA formulations can slow down disease progression.
“Therefore, the supplement of desired enzymes by lipid nanoparticle–mRNA formulations can slow down disease progression42,221.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [42]
After i.v. injection of OTC mRNA with HMT, prolonged survival was observed in OTCD mice, with no obvious changes of cytokines or significant pathological lesions in blood and liver.
“After i.v. injection of OTC mRNA with HMT, a prolonged survival was observed in OTCD mice. Meanwhile, no obvious changes of cytokines or significant pathological lesions were detected in the blood and liver, respectively.[177]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [177]
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References 59 · Cited by 145
- Authors
- Prieve, M. G., Harvie, P., Monahan, S. D., Roy, D., Li, A. G., Blevins, T. L., Paschal, A. E., Waldheim, M., Bell, E. C., Galperin, A., Ella-Menye, J.-R., & Houston, M. E.
- Corresponding author
- Prieve, Mary G.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 26
- Issue
- 3
- Pages
- 801-813
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5910669
- OpenAlex
- W2782155349
- Cited by
- 145
- References
- 59
- Citations by year
- 2026: 11 · 2025: 13 · 2024: 31 · 2023: 21 · 2022: 27 · 2021: 14 · 2020: 15 · 2019: 10 · 2018: 3
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- PhaseRx, Inc.
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- ornithine transcarbamylase deficiency, mRNA therapeutics, lipid nanoparticles, hepatocyte targeting, endosomal escape, blood ammonia, mouse model
- MeSH terms
- Animals, Disease Models, Animal, Male, Micelles, Ornithine Carbamoyltransferase, Polymers, RNA, Messenger, Urea, Genetic Therapy, Mice, Knockout, Ornithine Carbamoyltransferase Deficiency Disease, RNA, Small Interfering, Nanotechnology, Mice, Nanoparticles, Metabolic Networks and Pathways
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