Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe ornithine transcarbamylase deficiency.

Abstract

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder, characterized by hyperammonemia and accompanied by a high unmet patient need. mRNA therapies have been shown to be efficacious in hypomorphic Sparse-fur abnormal skin and hair (Spf-ash) mice, a model of late-onset disease. However, studying the efficacy of ornithine transcarbamylase (OTC) mRNA therapy in traditional knockout mice, a model for severe early-onset OTCD, is hampered by the rapid lethality of the model, and poor lipid nanoparticle (LNP) uptake into neonatal mouse liver. We developed a novel tamoxifen-inducible mouse to study the effect of mRNA therapy in the context of complete or near-complete OTC loss in adult animals. Characterization of the model showed that it is highly reproducible, 100% penetrant, and phenocopies hallmarks of human disease, with animals exhibiting decreased body weight, hyperammonemia, and brain edema. Delivery of OTC mRNA increased survival, maintained body weight, delayed the onset of hyperammonemia, and reduced brain edema. Therefore, this model provides a platform to study LNP-mediated mRNA therapies for the treatment of late-onset OTCD.