Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model.

Autor:	Zhao XJ; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Mohsen AW; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA., Mihalik S; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Solo K; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Basu S; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Aliu E; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Shi H; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Kochersberger C; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Karunanidhi A; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Van't Land C; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA., Coughlan KA; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Siddiqui S; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Rice LM; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Hillier S; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Guadagnin E; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., DeAntonis C; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Giangrande PH; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Martini PGV; Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA., Vockley J; Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA.; Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Jul 04; Vol. 32 (14), pp. 2347-2356.
DOI:	10.1093/hmg/ddad076
Abstrakt:	Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm-/- mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm-/- mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm-/- mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm-/- mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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