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

被引：6

作者：

Zhao, Xue-Jun ^{[1
]}

Mohsen, Ai-Walid ^{[1
,2
]}

Mihalik, Stephanie ^{[1
]}

Solo, Keaton ^{[1
]}

Basu, Shakuntala ^{[1
]}

Aliu, Ermal ^{[1
]}

Shi, Huifang ^{[1
]}

Kochersberger, Catherine ^{[1
]}

Karunanidhi, Anuradha ^{[1
]}

Van't Land, Clinton ^{[1
]}

Coughlan, Kimberly A.

Siddiqui, Summar ^{[3
]}

Rice, Lisa M. ^{[3
]}

Hillier, Shawn ^{[3
]}

Guadagnin, Eleonora ^{[3
]}

DeAntonis, Christine ^{[3
]}

Giangrande, Paloma H. ^{[3
]}

Martini, Paolo G., V ^{[3
]}

Vockley, Jerry ^{[1
,2
,4
]}

机构：

[1] Univ Pittsburgh, Div Genet & Genom Med, Pittsburgh, PA 15224 USA

[2] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA

[3] Moderna Therapeut, Rare Dis, Cambridge, MA 02139 USA

[4] Univ Pittsburgh, Dept Pediat, Div Genet & Genom Med, 4401 Penn Ave, Pittsburgh, PA 15224 USA

来源：

HUMAN MOLECULAR GENETICS | 2023年 / 32卷 / 14期

关键词：

FATTY-ACID OXIDATION; LIPID NANOPARTICLES; MICE; DIAGNOSIS; DEFECTS; DISORDERS; DELIVERY; PROTEIN;

D O I：

10.1093/hmg/ddad076

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2347 / 2356

页数：10

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