Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia.

Abstract

Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a pseudoU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%-85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice.

• Authors: Ding An, Jessica L Schneller, Andrea Frassetto, Shi Liang, Xuling Zhu, Ji-Sun Park, Matt Theisen, Sue-Jean Hong, Jenny Zhou, Raj Rajendran, Becca Levy, Rebecca Howell, Gilles Besin, Vladimir Presnyak, Staci Sabnis, Kerry E Murphy-Benenato, E Sathyajith Kumarasinghe, Timothy Salerno, Cosmin Mihai, Christine M Lukacs, Randy J Chandler, Lin T Guey, Charles P Venditti, Paolo G V Martini
• Journal: Cell reports (Cell Rep) Vol. 21 Issue 12 Pg. 3548-3558 (Dec 19 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 29262333 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Lipids
• RNA, Messenger
• Methylmalonyl-CoA Mutase

Topics

• Administration, Intravenous
• Amino Acid Metabolism, Inborn Errors (therapy)
• Animals
• Female
• Genetic Therapy (methods)
• Humans
• Lipids (chemistry)
• Liver (metabolism)
• Male
• Methylmalonyl-CoA Mutase (genetics, metabolism)
• Mice
• Nanoparticles (administration & dosage, chemistry)
• RNA, Messenger (genetics, metabolism)