Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency

Abstract

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.

mRNA as novel technology for passive immunotherapy

“…Thereafter, it took almost two decades until further studies started to demonstrate the broad potential of mRNA-based protein therapies. Meanwhile, there is a plethora of publications on a huge variety of indications comprising anemia [188,218], hemophilia [223,224], myocardial infarction [155,225], cancer [226,227], lung disease such as surfactant B deficiency and asthma [228][229][230], metabolic disorders [231][232][233][234][235], fibrosis [195], skeletal degeneration [236], tendon impairment [237], and neurological disorders such as sensory nerve dysfunction, Friedreich's ataxia and Alzheimer's disease [238][239][240]. Whereas evidence for the therapeutic potential of mRNA is mostly restricted to mouse models, first data in swine indicate that mRNA-based protein therapies are feasible also in large animals [218,225].…”

“…Only very few studies looking at local administration used uncomplexed and thus unprotected mRNA [225,228,230,237]. The majority of investigations built on lipid-based formulations with a clear tendency to the application of LNPs [223,224,[231][232][233]239]. Most if not all groups purified their IVT mRNA before in vivo administration.…”

“…While some simply precipitated the mRNA [195,227,236], most used commercial purification kits. Only a few researchers applied HPLC purification [188,218,232]. With respect to the mRNA, the vast majority of studies used long poly(A) tails of at least 100 nucleotides.…”

Messenger RNA therapy for rare genetic metabolic diseases

“…A recent study addressed the efficacy and tolerability of mRNA-based therapy for OTC deficiency using the HMT two-nanoparticle mRNA delivery technology described above20 (figure 4). Administration of a single dose of human HTM/OTC mRNA (hOTC) to Otc spf-ash mice resulted in widespread mitochondrial hOTC protein expression across the liver parenchyma and in increased OTC enzymatic activity up to 10 days after mRNA injection.…”

Biomedical applications of mRNA nanomedicine

“…Intravenous administration of the therapeutic into two murine models of methylmalonic acidemia resulted in robust hepatic MUT expression and improved growth and survival of mice. In a recent study, a hybrid mRNA delivery system comprising a lipid nanoparticle for mRNA protection and a polymer micelle for hepatocytes targeting was used to deliver human ornithine transcarbamylase mRNA in a murine model of ornithine transcarbamylase deficiency, which led to pronounced synthesis of the desired protein in the liver and prolonged survival [173]. …”