TY - JOUR
T1 - Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model
AU - Zhao, Xue Jun
AU - Mohsen, Ai Walid
AU - Mihalik, Stephanie
AU - Solo, Keaton
AU - Basu, Shakuntala
AU - Aliu, Ermal
AU - Shi, Huifang
AU - Kochersberger, Catherine
AU - Karunanidhi, Anuradha
AU - Van't Land, Clinton
AU - Coughlan, Kimberly A.
AU - Siddiqui, Summar
AU - Rice, Lisa M.
AU - Hillier, Shawn
AU - Guadagnin, Eleonora
AU - Deantonis, Christine
AU - Giangrande, Paloma H.
AU - Martini, Paolo G.V.
AU - Vockley, Jerry
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].
PY - 2023/7/15
Y1 - 2023/7/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddad076
DO - 10.1093/hmg/ddad076
M3 - Article
C2 - 37162351
AN - SCOPUS:85164242926
SN - 0964-6906
VL - 32
SP - 2347
EP - 2356
JO - Human molecular genetics
JF - Human molecular genetics
IS - 14
ER -