Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency

We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases. In this issue of Molecular Therapy, Prieve et al. describe a novel, targeted mRNA delivery system that corrects a rare liver disease in a murine model of ornithine transcarbamylase deficiency having a single enzyme defect. This non-viral delivery method allows multi-dose, systemic administration for treatment of inherited metabolic diseases.