Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates
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Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-α-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of α-Gal A in tissues and plasma. Single intravenous administration of h-α-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-α-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.
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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 [224]
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- Authors
- Zhu, X., Yin, L., Theisen, M., Zhuo, J., Siddiqui, S., Levy, B., Presnyak, V., Frassetto, A., Milton, J., Salerno, T., Benenato, K. E., Milano, J., Lynn, A., Sabnis, S., Burke, K., Besin, G., Lukacs, C. M., Guey, L. T., Finn, P. F., & Martini, P. G. V.
- Corresponding author
- Martini, Paolo G.V.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 104
- Issue
- 4
- Pages
- 625-637
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6451694
- OpenAlex
- W2921621642
- Cited by
- 165
- References
- 51
- Citations by year
- 2026: 12 · 2025: 30 · 2024: 26 · 2023: 20 · 2022: 32 · 2021: 23 · 2020: 14 · 2019: 8
- FWCI
- 13.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Moderna
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Fabry disease, alpha-galactosidase A, globotriaosylceramide, lysosomal storage disease, enzyme replacement therapy, pharmacokinetics, pharmacodynamics, non-human primates, substrate reduction, X-linked disorders
- MeSH terms
- alpha-Galactosidase, Fabry Disease, Animals, Disease Models, Animal, Endocytosis, Humans, Lipids, Lysosomes, Macaca fascicularis, Male, RNA, Messenger, Tissue Distribution, Trihexosylceramides, Genetic Therapy, Mice, Knockout, Mice, Enzyme Replacement Therapy
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