Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia
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
Affiliations
Ding An
Moderna Therapeutics, Cambridge, MA 02139, USA
Jessica L. Schneller
Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Andrea Frassetto
Moderna Therapeutics, Cambridge, MA 02139, USA
Shi Liang
Moderna Therapeutics, Cambridge, MA 02139, USA
Xuling Zhu
Moderna Therapeutics, Cambridge, MA 02139, USA
Ji-Sun Park
Moderna Therapeutics, Cambridge, MA 02139, USA
Matt Theisen
Moderna Therapeutics, Cambridge, MA 02139, USA
Sue-Jean Hong
Moderna Therapeutics, Cambridge, MA 02139, USA
Jenny Zhou
Moderna Therapeutics, Cambridge, MA 02139, USA
Raj Rajendran
Moderna Therapeutics, Cambridge, MA 02139, USA
Becca Levy
Moderna Therapeutics, Cambridge, MA 02139, USA
Rebecca Howell
Moderna Therapeutics, Cambridge, MA 02139, USA
Gilles Besin
Moderna Therapeutics, Cambridge, MA 02139, USA
Vladimir Presnyak
Moderna Therapeutics, Cambridge, MA 02139, USA
Staci Sabnis
Moderna Therapeutics, Cambridge, MA 02139, USA
Kerry E. Murphy-Benenato
Moderna Therapeutics, Cambridge, MA 02139, USA
E. Sathyajith Kumarasinghe
Moderna Therapeutics, Cambridge, MA 02139, USA
Timothy Salerno
Moderna Therapeutics, Cambridge, MA 02139, USA
Cosmin Mihai
Moderna Therapeutics, Cambridge, MA 02139, USA
Christine M. Lukacs
Moderna Therapeutics, Cambridge, MA 02139, USA
Randy J. Chandler
Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
Lin T. Guey
Moderna Therapeutics, Cambridge, MA 02139, USA
Charles P. Venditti
Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Corresponding author
Paolo G.V. Martini
Moderna Therapeutics, Cambridge, MA 02139, USA; Corresponding author
Summary: 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 5-methoxyU-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. : An et al. find that systemically delivered LNP-encapsulated mRNA results in hepatic protein expression. hMUT mRNA expresses functional mitochondrial MUT enzyme, and MMA mouse models show a metabolic and clinical response after mRNA therapy. Keywords: methylmalonic acidemia/aciduria, methylmalonyl-CoA mutase, methylmalonic acid, mRNA therapy, lipid nanoparticle, liver
