Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Open Access
- 21 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-10
- https://doi.org/10.1038/s41467-020-19156-3
Abstract
Propionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders.This publication has 42 references indexed in Scilit:
- Simple, Fast, and Simultaneous Detection of Plasma Total Homocysteine, Methylmalonic Acid, Methionine, and 2-Methylcitric Acid Using Liquid Chromatography and Mass Spectrometry (LC/MS/MS)JIMD Reports, 2013
- Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patientsOrphanet Journal of Rare Diseases, 2013
- Acute management of propionic acidemiaMolecular Genetics and Metabolism, 2012
- Natural history of propionic acidemiaMolecular Genetics and Metabolism, 2012
- Crystal structure of the α6β6 holoenzyme of propionyl-coenzyme A carboxylaseNature, 2010
- Cardiomyopathies in Propionic Aciduria are Reversible After Liver TransplantationThe Journal of Pediatrics, 2010
- Combined Newborn Screening for Succinylacetone, Amino Acids, and Acylcarnitines in Dried Blood SpotsClinical Chemistry, 2008
- Rapid 2nd-Tier Test for Measurement of 3-OH-Propionic and Methylmalonic Acids on Dried Blood Spots: Reducing the False-Positive Rate for Propionylcarnitine during Expanded Newborn Screening by Liquid Chromatography–Tandem Mass SpectrometryClinical Chemistry, 2007
- Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coliOnline Journal of Public Health Informatics, 2005
- Potential relationship between genotype and clinical outcome in propionic acidaemia patientsEuropean Journal of Human Genetics, 2000