mRNA-Based Therapy for Liver-Targeted Monogenic Disorders

mRNA-based therapy represents a promising solution for genetic metabolic diseases, which are currently lacking effective treatments. Here, we give a brief introduction to liver-mediated mRNA therapy for rare genetic conditions, including methylmalonic acidaemia and ornithine transcarbamylase deficiency. Besides, to assist and promote the research of mRNA-based therapy for rare genetic metabolic diseases, Creative Biogene is offering a wide series of mRNA research services. We continuously challenge ourselves and strive to offer our customers the finest service.

mRNA—a therapeutic tool for liver-targeted monogenic disorders

One of the functions of the liver is to synthesize a variety of macromolecules, and this ability can be utilized to overexpress heterologous proteins. Some proteins exert therapeutic activity at different subcellular localisations in the hepatocytes, while other proteins must be secreted and act on the distant targeted organs. Therefore, the liver could be a target for mRNA therapies designed for the treatment of monogenic disorders in terms of overcoming the inability of mutated genes to produce active proteins. mRNA can use the human body to produce any type of protein. In addition, mRNA-based strategy can preserve the natural localisation of the therapeutic protein in different organelles as well as support natural post-translational modifications.

mRNA therapy for methylmalonic acidaemia

Methylmalonic acidemia (MMA) is a devastating metabolic disorder for which there is currently no approved treatment. MMA is primarily caused by partial (mut-) or complete (mut0) loss of methylmalonyl-CoA mutase (MUT), a vitamin B12-dependent mitochondrial enzyme that takes part in the terminal step of isoleucine, valine, and odd chained fatty acid oxidation. The MUT gene is ubiquitously expressed, and its deficiency is associated with profound biochemical derangements, leading to multisystemic complications. These complications are more obvious in tissues and organs with high metabolic demand, such as the brain, eyes, heart and kidneys. Since the restoration of MUT activity in the liver is suggested as a therapeutic strategy for the treatment of MMA. It is reported that human methylmalonyl-CoA mutase (hMUT) mRNA can express functional mitochondrial MUT enzyme in mouse livers. And after mRNA therapy, a metabolic and clinical response was observed in MMA mouse models.

Strategy of hMUT mRNA therapy.Fig 1. Strategy of hMUT mRNA therapy. (An, D., et al., 2017)

mRNA therapy for ornithine transcarbamylase deficiency

Mitochondrial ornithine transcarbamoylase (OTC) is involved in removing excess nitrogen from the body and entering the urea cycle. OTC deficiency can cause hyperammonaemia, which is an elevated concentration of ammonia in the bloodstream. The accumulation of ammonia may lead to neurological damage, coma and even lethality. And the deficiency is the most common inborn error of the urea cycle. In addition to limited interventions for OTC deficiency, there are other therapeutic options, such as liver transplantation and gene-based therapy. A recent study has demonstrated that hybrid mRNA technology delivery system (HMT) delivery of human OTC mRNA normalizes plasma ammonia as well as urinary orotic acid levels. OTC mRNA leads to a prolonged survival benefit in the murine model of ornithine transcarbamylase deficiency (OTCD). The HMT is comprised of an inert lipid nanoparticle and a polymer micelle, protect the mRNA from nucleases and promote the release of mRNA in targets hepatocytes, respectively. As a unique non-viral mRNA delivery method, HMT is able to treat single-gene inherited metabolic diseases with multi-dose, systemic administration.

The hybrid mRNA technology delivery system. (A) Key  components of HMT include a polymer micelle and LNP. (B) Graphic illustrates  the in vivo delivery protocol and release of mRNA into the cytoplasm of  hepatocytes for protein production.Fig 2. The hybrid mRNA technology delivery system. (A) Key components of HMT include a polymer micelle and LNP. (B) Graphic illustrates the in vivo delivery protocol and release of mRNA into the cytoplasm of hepatocytes for protein production. (Prieve, M. G., et al., 2018)

Creative Biogene is a leading service provider for mRNA-based drug research and development. Our extensive experience, an excellent team of experts, and advanced technology platforms make us an ideal partner for worldwide customers. We can support our customers with the most affordable, high-quality custom mRNAs according to the desired applications. If you are interested in our services, please don't hesitate to contact us. We look forward to providing services for your next project.


  1. An, D., et al. (2017). "Systemic messenger RNA therapy as a treatment for methylmalonic acidemia." Cell reports, 21(12), 3548-3558.
  2. Prieve, M. G., et al. (2018). "Targeted mRNA therapy for ornithine transcarbamylase deficiency." Molecular Therapy, 26(3), 801-813.

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