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.

mRNA as novel technology for passive immunotherapy

“…Similar to the Weissman work, Thran and colleagues observed a disproportionate increase of antibody serum titers with elevated mRNA doses. Onset of antibody expression was rather rapid, being already substantial 2 h after injection and reaching peak levels after approximately 4 h. This confirms findings on other mRNA-mediated protein therapies showing that mRNA starts accumulating in hepatocytes within minutes after administration and leads to substantial protein levels within a couple of hours [223,231]. Serum half-life of IgG antibodies appeared to be in the range of 1 week and thus slightly longer compared to Pardi et al [267].…”

“…However, this can in principle be counteracted by optimization towards better biocompatibility. In case of LNPs, fast degradation was shown to be particularly important [231,232,269].…”

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…An et al demonstrate that for MMA, intravenous administration of mRNA encoding Mut using a biodegradable lipid nanoparticle, results in a 75% reduction of plasma methylmalonic acid and increased MCM activity in the liver of Mut −/− mice, and that repeated dosing led to weight gain and improved survival. To the best of our knowledge, no mRNA treatment for PA has been reported.…”

Messenger RNA therapy for rare genetic metabolic diseases

“…These works provided proof-of-concept evidence for the therapeutic value of hepatic MUT activity restoration, as Mut -/- mice were rescued from neonatal mortality and impaired growth in spite of a partial correction of plasma methylmalonic acid levels. With these precedents, the potential of mRNA treatment for MMA has also been recently explored 8. Systemic administration of human MUT (hMUT) mRNA formulated in LNPs as described above demonstrated a rapid (as early as 2 hours after intravenous injection) and sustained expression of hMUT protein in mouse livers (figure 4).…”

“…Systemic administration of human MUT (hMUT) mRNA formulated in LNPs as described above demonstrated a rapid (as early as 2 hours after intravenous injection) and sustained expression of hMUT protein in mouse livers (figure 4). The therapeutic capacity of this hMUT mRNA was tested in two clinically relevant mouse models: Mut -/- mice rescued from perinatal lethality by transgenic expression of MUT in skeletal muscle, and transgenic Mut -/- mice expressing the p.G715V MUT mutant variant found in patients with MMA 8. In the first model, hMUT mRNA administration resulted in a rapid reduction of methylmalonic acid levels in plasma and tissues, including liver, kidney, brain, heart and skeletal muscle.…”