Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia

Abstract

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