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Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model,
Xuling Zhu1, Ling Yin1, Matt Theisen1
1Moderna Inc, 200 Technology Square, Cambridge, MA 02139, USA.
Abstract:
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.
Insights
Messenger RNA (mRNA) therapy shows promise for Fabry disease, a rare genetic disorder. Preclinical studies in animal models demonstrate that systemic mRNA encoding alpha-galactosidase A effectively reduces disease substrate, offering a potential new treatment avenue.
Area of Science:
- Genetics and Genetic Diseases
- Biochemistry
- Pharmacology
Background:
- Fabry disease is an X-linked lysosomal storage disorder resulting from deficient alpha-galactosidase A (α-Gal A) activity.
- Accumulation of globotriaosylceramide and related compounds causes progressive organ damage.
- Current enzyme replacement therapy (ERT) has limitations, necessitating novel therapeutic strategies.
Purpose of the Study:
- To evaluate the preclinical efficacy and safety of systemic messenger RNA (mRNA) encoding human α-Gal A for Fabry disease treatment.
- To assess the pharmacokinetics, biodistribution, and therapeutic effects of mRNA-based α-Gal A delivery across species.
Main Methods:
- Systemic administration of mRNA encoding human α-Gal A was tested in wild-type mice, α-Gal A-deficient mice, and wild-type non-human primates (NHPs).
- Evaluated protein activity, substrate levels in plasma and tissues, pharmacokinetics, and safety profiles.
- Dose-response, single-dose, and repeat-dose studies were conducted.
Main Results:
- mRNA therapy led to prolonged expression of α-Gal A protein in mice, with sustained substrate reduction for up to six weeks after a single dose.
- Dose-dependent increases in enzyme activity and reductions in substrate levels were observed in deficient mice.
- Repeat administrations in a Fabry mouse model demonstrated sustained efficacy, and studies in NHPs confirmed safety and translatability.
Conclusions:
- Systemic mRNA therapy represents a viable preclinical proof-of-concept for treating Fabry disease.
- This approach holds potential for treating other lysosomal storage disorders.
- mRNA-based gene therapy offers a promising alternative to conventional treatments.
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