mRNA-based therapy proves superior to the standard of care for treating hereditary tyrosinemia 1 in a mouse model.

Autor:	Cacicedo ML; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Weinl-Tenbruck C; CureVac AG, Friedrich-Miescher-Str. 15, 72076 Tübingen, Germany., Frank D; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Wirsching S; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Straub BK; Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Hauke J; Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Okun JG; Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany., Horscroft N; MRM Health, Technologiepark, 739052 Zwijnaarde, Belgium., Hennermann JB; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Zepp F; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany., Chevessier-Tünnesen F; CureVac AG, Friedrich-Miescher-Str. 15, 72076 Tübingen, Germany., Gehring S; Children's Hospital, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2022 Jul 15; Vol. 26, pp. 294-308. Date of Electronic Publication: 2022 Jul 15 (Print Publication: 2022).
DOI:	10.1016/j.omtm.2022.07.006
Abstrakt:	Hereditary tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by deficiency of fumarylacetoacetate hydrolase (FAH). Only limited treatment options (e.g., oral nitisinone) are available. Patients must adhere to a strict diet and face a life-long risk of complications, including liver cancer and progressive neurocognitive decline. There is a tremendous need for innovative therapies that standardize metabolite levels and promise normal development. Here, we describe an mRNA-based therapeutic approach that rescues Fah -deficient mice, a well-established tyrosinemia model. Repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA resulted in FAH protein synthesis in deficient mouse livers, stabilized body weight, normalized pathologic increases in metabolites after nitisinone withdrawal, and prevented early death. Dose reduction and extended injection intervals proved therapeutically effective. These results provide proof of concept for an mRNA-based therapeutic approach to treating hereditary tyrosinemia type 1 that is superior to the standard of care. Competing Interests: C.W. and F.C. are salaried employees of CureVac AG, Tübingen, Germany. N.H. was salaried employee of CureVac AG, Tübingen, Germany at the beginning of the project; and is salaried employee of MRM Health, Zwijnaarde, Belgium. M.L.C., D.F., S.W., S.G., B.K.S., J.H., J.G.O., J.B.H., and F.Z. declare no competing interests. (© 2022 The Author(s).)
Databáze:	MEDLINE
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