Lipid nanoparticle-targeted mRNA therapy as a treatment for the inherited metabolic liver disorder arginase deficiency

Significance Systemically administered lipid nanoparticles (LNPs) targeting the liver were able to express the cytoplasmic enzyme arginase 1 (ARG1) in a conditional knockout model of ARG1 deficiency. Metabolically, this resulted in maintaining normal plasma ammonia and arginine, preventing the build-up of excessive hepatic arginine, and obviated the development of guanidino compounds, a hallmark of this enzyme deficiency. Unlike controls, repeat dosing of LNPs encapsulating human codon-optimized ARG1 messenger RNA led to long-term survival without evidence of toxicity, restoration of ureagenesis, and the ability to handle toxic ammonia loading. These findings have implications for therapy of ARG1 deficiency, which is presently inadequately treated and leads to progressive neurological decline.