PMID- 37162351 OWN - NLM STAT- MEDLINE DCOM- 20230707 LR - 20240511 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 32 IP - 14 DP - 2023 Jul 4 TI - Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model. PG - 2347-2356 LID - 10.1093/hmg/ddad076 [doi] AB - Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid beta-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. CI - (c) The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Zhao, Xue-Jun AU - Zhao XJ AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Mohsen, Ai-Walid AU - Mohsen AW AUID- ORCID: 0000-0002-0096-5959 AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. AD - Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA. FAU - Mihalik, Stephanie AU - Mihalik S AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Solo, Keaton AU - Solo K AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Basu, Shakuntala AU - Basu S AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Aliu, Ermal AU - Aliu E AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Shi, Huifang AU - Shi H AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Kochersberger, Catherine AU - Kochersberger C AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Karunanidhi, Anuradha AU - Karunanidhi A AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Van't Land, Clinton AU - Van't Land C AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. FAU - Coughlan, Kimberly A AU - Coughlan KA AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Siddiqui, Summar AU - Siddiqui S AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Rice, Lisa M AU - Rice LM AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Hillier, Shawn AU - Hillier S AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Guadagnin, Eleonora AU - Guadagnin E AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - DeAntonis, Christine AU - DeAntonis C AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Giangrande, Paloma H AU - Giangrande PH AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Martini, Paolo G V AU - Martini PGV AD - Moderna Therapeutics, Rare Diseases, Cambridge, MA, 02139, USA. FAU - Vockley, Jerry AU - Vockley J AD - Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, 15224, USA. AD - Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, 15261, USA. LA - eng GR - R01 DK78755/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - EC 1.3.8.7 (Acyl-CoA Dehydrogenase) RN - 0 (RNA, Messenger) RN - EC 1.3.- (Acyl-CoA Dehydrogenases) RN - Medium chain acyl CoA dehydrogenase deficiency SB - IM EIN - Hum Mol Genet. 2023 Aug 7;32(16):2679. PMID: 37466444 MH - Humans MH - Mice MH - Animals MH - Acyl-CoA Dehydrogenase/genetics/metabolism MH - RNA, Messenger/genetics MH - Disease Models, Animal MH - *Fibroblasts/metabolism MH - *Acyl-CoA Dehydrogenases PMC - PMC10321387 EDAT- 2023/05/10 12:42 MHDA- 2023/07/07 06:42 PMCR- 2024/05/10 CRDT- 2023/05/10 10:04 PHST- 2023/02/28 00:00 [received] PHST- 2023/05/01 00:00 [revised] PHST- 2023/05/08 00:00 [accepted] PHST- 2023/07/07 06:42 [medline] PHST- 2023/05/10 12:42 [pubmed] PHST- 2023/05/10 10:04 [entrez] PHST- 2024/05/10 00:00 [pmc-release] AID - 7159202 [pii] AID - ddad076 [pii] AID - 10.1093/hmg/ddad076 [doi] PST - ppublish SO - Hum Mol Genet. 2023 Jul 4;32(14):2347-2356. doi: 10.1093/hmg/ddad076.