Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia

Lei Jiang, Ji-Sun Park, Ling Yin, Rodrigo Laureano, Eric Jacquinet, Jinsong Yang, Shi Liang, Andrea Frassetto, Jenny Zhuo, Xinhua Yan, Xuling Zhu, Steven Fortucci, Kara Hoar, Cosmin Mihai, Christopher Tunkey, Vlad Presnyak, Kerry E. Benenato, Christine M. Lukacs, Paolo G. V. Martini () and Lin T. Guey ()
Additional contact information
Lei Jiang: Moderna Inc., 200 Technology Square
Ji-Sun Park: Moderna Inc., 200 Technology Square
Ling Yin: Moderna Inc., 200 Technology Square
Rodrigo Laureano: Moderna Inc., 200 Technology Square
Eric Jacquinet: Moderna Inc., 200 Technology Square
Jinsong Yang: Moderna Inc., 200 Technology Square
Shi Liang: Moderna Inc., 200 Technology Square
Andrea Frassetto: Moderna Inc., 200 Technology Square
Jenny Zhuo: Moderna Inc., 200 Technology Square
Xinhua Yan: Moderna Inc., 200 Technology Square
Xuling Zhu: Moderna Inc., 200 Technology Square
Steven Fortucci: Moderna Inc., 200 Technology Square
Kara Hoar: Moderna Inc., 200 Technology Square
Cosmin Mihai: Moderna Inc., 200 Technology Square
Christopher Tunkey: Moderna Inc., 200 Technology Square
Vlad Presnyak: Moderna Inc., 200 Technology Square
Kerry E. Benenato: Moderna Inc., 200 Technology Square
Christine M. Lukacs: Moderna Inc., 200 Technology Square
Paolo G. V. Martini: Moderna Inc., 200 Technology Square
Lin T. Guey: Moderna Inc., 200 Technology Square

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19156-3

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