Human VLCAD (hVLCAD) mRNA can reverse the metabolic effects of VLCAD deficiency, a type of long-chain fatty acid oxidation disorder (LCFAOD) and generate functional very long-chain acyl-CoA dehydrogenase (VLCAD) enzyme in cell culture and in a mouse model of the disease, according to a study presented at the 2023 lecture series of the International Network for Fatty Acid Oxidation Research and Management (INFORM) and published in the Molecular Genetics and Metabolism.
These findings support the use of hVLCAD mRNA as a potential therapy for patients with VLCAD deficiency.
Read more about the etiology of LCFAOD
To explore the potential of mRNA as a therapeutic option for VLCAD deficiency, Xue-Jun Zhao, MSc, MD, and colleagues from the University of Pittsburgh, Pennsylvania, and Moderna Therapeutics in Cambridge, Massachusetts, used fibroblasts derived from mouse embryonic fibroblasts, patients with VLCAD deficiency, VLCAD knockout mice themselves, and hepatocytes from VLCAD knockout mice.
The results showed that hVLCAD mRNA transfection led to high expression levels of VLCAD enzyme in all cell types. This highly expressed enzyme localized to mitochondria within cells and was active.
When they administered lipid nanoparticle encapsulated hVLCAD mRNA (LNP-VLCAD) into the bloodstream of VLCAD knockout mice, Dr. Zhao and colleagues saw that there were significant amounts of VLCAD protein in the liver of the animals. The level of protein then declined over a week.
These animals also had reduced hepatic steatosis, were more resistant to cold stress, and had less toxic metabolite accumulation in the blood compared to animals that were not treated with LNP-VLCAD.
“This therapeutic approach has potential for the treatment of VLCAD deficient patients,” Dr. Zhao concluded, “and a similar approach may see application in other metabolic disorders.”
VLCAD deficiency is 1 of the most common inborn errors of long-chain fatty acid beta-oxidation. It is characterized by hypoglycemia, cardiomyopathy, and skeletal myopathy with recurrent rhabdomyolysis.
Zhao XJ. Synthetic messenger RNA rescues very long-chain acyl-A dehydrogenase deficiency in a murine model. Lecture presented at the International Network for Fatty Acid Oxidation Research and Management (INFORM) 2023 lecture series: February 20, 2023; Virtual.
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 23, 2022. doi:10.1016/j.ymgme.2022.106982