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Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy
Open accessAbstract
Fabry disease is a lysosomal storage disorder caused by the deficiency of α-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human α-galactosidase protein in vivo via nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human α-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as ∼1,330-fold over normal physiological values.
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“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 [225]
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RNA-based therapeutic interventions for the management of Anderson-Fabry disease
Cagnin, S. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102679
mRNA-based therapies: current progress and future prospects for treating kidney disease
Song, Y., & Su, H. (2025) · Clinical and Experimental Nephrology · doi:10.1007/s10157-025-02785-7
Zhang, X., Liao, Y., Hong, X., Xiao, Y., & Zeng, X. (2026) · Science China Chemistry · doi:10.1007/s11426-025-3182-6
Engineering mRNA therapeutics for protein supplementation: Challenges and future horizons
Tao, Y., Zhao, Y., Su, Q., Pan, J., Yin, J., & Xu, C. (2024) · BME Horizon · doi:10.70401/bmeh.2026.0025
Self-citationCurrent progress in developing mRNA-lipid nanoparticle vaccines against human bacterial pathogens
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Pain in Fabry disease: do experimental models reveal novel therapeutic targets?
Galimberti, G., Riboldi, B., Amodeo, G., Franchi, S., Braganti, C., Sacerdote, P., & Ceruti, S. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118323
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RNA vaccines in motion: A multidisciplinary exploration of design, delivery, and deployment
Abuhassan, Q., Aldulaimi, A., Waleed, O. S., Ganesan, S., Kavitha, V., Maharana, L., Sharma, R., Latipova, M., Madatova, N., Jumanazarov, D., et al. (2026) · Bioimpacts · doi:10.34172/bi.33056
Metadata
- Authors
- DeRosa, F., Smith, L., Shen, Y., Huang, Y., Pan, J., Xie, H., Yahalom, B., & Heartlein, M. W.
- Affiliations
- Translate Bio (United States) (US)
- Shire (United States) (US)
- Corresponding author
- Heartlein, Michael W.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 27
- Issue
- 4
- Pages
- 878-889
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC6453518
- OpenAlex
- W2922121037
- Cited by
- 111
- References
- 68
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 19 · 2021: 14 · 2020: 13 · 2019: 5
- FWCI
- 8.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Shire
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- Fabry disease, alpha-galactosidase A, mRNA therapeutics, sustained protein delivery, enzyme replacement therapy, lysosomal storage disease, nonhuman primate model
- MeSH terms
- alpha-Galactosidase, Fabry Disease, Animals, Callithrix, Disease Models, Animal, Drug Compounding, Female, Humans, Kidney, Lipids, Liver, Male, RNA, Messenger, Drug Delivery Systems, Treatment Outcome, Mice, Knockout, Mice, Nanoparticles, Gene Knockout Techniques, Enzyme Replacement Therapy
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