Characterizing the Mechanism of Action for mRNA Therapeutics for the Treatment of Propionic Acidemia, Phenylketonuria, and Methylmalonic Acidemia

Lipid nanoparticles carrying messenger RNA (mRNA) therapies show promise for treating metabolic disorders caused by a lack of proteins, such as propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). We present findings from preclinical assessments of mRNA-3927 (a potential PA treatment), mRNA-3705 (a potential MMA treatment), and mRNA-3210 (a potential PKU treatment) using mouse models for each condition. All three mRNA treatments demonstrated positive pharmacokinetic and pharmacodynamic (PK/PD) reactions in their respective mouse models, indicated by changes in mRNA, protein levels, or activity, and reduced levels of relevant biomarkers compared to animals receiving a control treatment. These preclinical results helped develop PK/PD models that, when adjusted for human size, predict the initial doses for human trials of each therapy. The estimated starting doses for humans are 0.3 mg/kg for mRNA-3927, 0.1 mg/kg for mRNA-3705, and 0.4 mg/kg for mRNA-3210, respectively.