Long-term efficacy and safety of mRNA therapy in two murine models of methylmalonic acidemia
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BACKGROUND: Isolated methylmalonic acidemia/aciduria (MMA) is an ultra-rare, serious, inherited metabolic disorder with significant morbidity and mortality. Exogenously delivered mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, is a potential therapy to produce functional MUT enzyme in liver. METHODS: Two 12-week repeat-dose studies were conducted to evaluate the efficacy and safety of intravenously-administered hMUT mRNA encapsulated in lipid nanoparticles in two murine models of MMA. FINDINGS: In MMA hypomorphic mice, hMUT mRNA treatment resulted in dose-dependent and reproducible biomarker responses after each dose. Enzymatically-active MUT protein was produced in liver in a dose-dependent manner. hMUT mRNA was well-tolerated with no adverse effects, as indicated by the lack of clinical observations, minimal changes in clinical chemistry parameters, and histopathology examination across all tissues. In severe MMA mice, hMUT mRNA led to substantially improved survival and growth and ameliorated biochemical abnormalities, all of which are cardinal clinical manifestations in severely affected patients. INTERPRETATION: These data demonstrate durable functional benefit of hMUT mRNA and support development of this new class of therapy for a devastating, pediatric disorder. FUND: This work was funded by Moderna, Inc.
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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 [228]
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References 49 · Cited by 87
- Authors
- An, D., Frassetto, A., Jacquinet, E., Eybye, M., Milano, J., DeAntonis, C., Nguyen, V., Laureano, R., Milton, J., Sabnis, S., Lukacs, C. M., & Guey, L. T.
- Affiliations
- Moderna Therapeutics (United States) (US)
- Corresponding author
- Guey, Lin T.
- Venue
- EBioMedicine
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 45
- Pages
- 519-528
- ISSN
- 2352-3964 (ISSN-L)
- PMC
- PMC6642332
- OpenAlex
- W2960789951
- Cited by
- 87
- References
- 49
- Citations by year
- 2026: 8 · 2025: 22 · 2024: 14 · 2023: 14 · 2022: 11 · 2021: 11 · 2020: 5 · 2019: 2
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- EBioMedicine (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Moderna, Inc.
- 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
- methylmalonic acidemia, methylmalonyl-CoA mutase, mRNA therapeutics, lipid nanoparticles, in vivo gene delivery, inborn errors of metabolism, repeated-dose toxicity, growth and survival
- MeSH terms
- Amino Acid Metabolism, Inborn Errors, Animals, Child, Disease Models, Animal, Humans, Lipids, Liver, Methylmalonyl-CoA Mutase, RNA, Messenger, Mice
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