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

Xue Jun Zhao, Ai Walid Mohsen, Stephanie Mihalik, Keaton Solo, Shakuntala Basu, Ermal Aliu, Huifang Shi, Catherine Kochersberger, Anuradha Karunanidhi, Clinton Van't Land, Kimberly A. Coughlan, Summar Siddiqui, Lisa M. Rice, Shawn Hillier, Eleonora Guadagnin, Christine Deantonis, Paloma H. Giangrande, Paolo G.V. Martini, Jerry Vockley

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2347-2356
Number of pages10
JournalHuman molecular genetics
Issue number14
StatePublished - Jul 15 2023

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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