The transfection of human very long-chain acyl-CoA dehydrogenase (hVLCAD) mRNA can generate functional VLCAD enzyme and reverse the metabolic effects of VLCAD deficiency, a type of long-chain fatty acid oxidation disorder (LCFAOD), found a new study published in the journal Molecular Genetics and Metabolism

“Our results identify mRNA as a viable therapeutic option for VLCAD [deficiency],” the study authors wrote.

Read more about the types of LCFAOD


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To investigate the potential of mRNA therapy in VLCAD deficiency, a team led by Jerry Vockley, MD, PhD, FACMG, from the University of Pittsburgh, Pennsylvania, transfected fibroblasts derived from patients with VLCAD deficiency, mouse embryonic fibroblasts, and hepatocytes from VLCAD knockout mice with synthetic hVLCAD mRNA. They also administered lipid nanoparticle encapsulated hVLCAD mRNA (LNP-VLCAD) to the bloodstream of VLCAD knockout mice.

They found that the transfection of hVLCAD mRNA led to high levels of VLCAD protein expression in all 3 cell types. This protein localized to the mitochondria and led to increased enzyme activity. 

The administration of LNP-VLCAD to the bloodstream of VLCAD knockout mice led to the production of a significant amount of VLCAD protein in the liver of the animals. This was sustained for more than a week, and these animals had reduced hepatic steatosis and were more resistant to cold stress compared to control untreated animals. Moreover, the accumulation of toxic metabolites in their blood was reduced compared to untreated mice.

“Results from this study support the potential for hVLCAD mRNA for treatment of VLCAD deficiency,” the researchers concluded.

VLCAD deficiency is a group of rare genetic disorders characterized by impaired fat metabolism resulting in acute energy production crises and chronic energy deficiency. 

Therapeutic options are limited for all types of LCFAOD, including VLCAD deficiency making them good candidates for mRNA therapies.

Reference

Zhao XJ, Mohsen AW, Mihalik S, et al. Synthetic mRNA rescues very long-chain acyl-CoA dehydrogenase deficiency in patient fibroblasts and a murine model. Mol Genet Metab. Published online December 27, 2022. doi:10.1016/j.ymgme.2022.106982