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.
S66rescued from neonatal lethality, yet experience massive elevations of the characteristic metabolites (methylmalonic and 2-methylcitric acid) because of the lack of hepatic Mut activity. Disease related metabolites were measured in plasma samples derived from Mut -/-;Tg INS-MCK-Mut mice (n=7) prior to AAV gene delivery. The mice were then injected via the retro-orbital route with 1.5X10 11 GC of either AAV8-hAAT-MUT or AAV8-CBA-MUT. At 10 days and 30 days post-treatment, mice treated with either vector showed a significant reduction in methylcitrate and methymalonic acid levels, with AAV8-CBA-MUT (n=2) treated mice manifesting methylcitrate and methylmalonic acid levels that trended lower than those measured in mice injected with AAV8-hAAT-MUT (n=4) at both time points. Further studies will be needed to precisely compare the differences between the hAAT and CBA promoters in MMA mouse models, but our preliminary results demonstrate that the Mut -/-;Tg INS-MCK-Mut mice can be used to easily ascertain hepatic correction of Mut deficiency, which should help inform the selection of regulatory elements that will provide maximal therapeutic efficacy to treat patients with MMA.
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