mRNA-Based Approaches to Treating Liver Diseases

Abstract

Diseases that affect the liver account for approximately 2 million deaths worldwide each year. The increasing prevalence of these diseases and the limited efficacy of current treatments are expected to stimulate substantial growth in the global market for therapeutics that target the liver. Currently, liver transplantation is the only curative option available for many liver diseases. Gene therapy represents a valuable approach to treatment. The liver plays a central role in a myriad of essential metabolic functions, making it an attractive organ for gene therapy; hepatocytes comprise the most relevant target. To date, viral vectors constitute the preferred approach to targeting hepatocytes with genes of therapeutic interest. Alternatively, mRNA-based therapy offers a number of comparative advantages. Clinical and preclinical studies undertaken to treat inherited metabolic diseases affecting the liver, cirrhosis and fibrosis, hepatocellular carcinoma, hepatitis B, and cytomegalovirus using lipid nanoparticle-encapsulated mRNAs that encode the therapeutic or antigenic protein of interest are discussed.

Keywords: cirrhosis; hepatocellular carcinoma; inherited metabolic diseases; lipid nanoparticles; therapeutic mRNA constructs.

Figure 1

mRNA vaccine/therapeutic protein construct.

Figure 2

Cellular uptake and expression of LNP-encapsulated mRNA constructs. Constructs encoding antigenic/therapeutic proteins are encapsulated in LNP to prevent degradation and to promote cellular uptake: (a) Uptake of the mRNA-LNP complex is mediated by endocytosis; (b) mRNA constructs are released from the endosome into the cytosol where they are translated by ribosomes; (c) the antigenic/therapeutic proteins are produced; (d) The protein products are sequestered intracellularly, incorporated into cell membranes or secreted. Figure was created with biorender.com (accessed on 19 August 2022).

Figure 3

Lipid nanoparticle-encapsulated mRNA construct. LNP-encapsulated mRNA constructs are composed of: (1) polyanionic mRNA bound by an ionizable lipid, (2) a zwitterionic phospholipid that helps package nucleic acids and stabilize LNPs, (3) cholesterol, which stabilizes the LNP lipid bilayer and promotes fusion with the cell membrane, and (4) lipid-anchored PEG, which reduces non-specific protein absorption, diminishes LNP aggregation and improves colloidal stability. Figure was created with biorender.com (accessed on 19 August 2022).

Figure 4

mRNA-based approach for enzyme replacement therapy. In general, mouse models for metabolic disorders from the liver constitute enzyme-deficient mice characterized by the accumulation of toxic serum concentrations of metabolites. mRNA-LNPs inoculated i.m. or i.v. are transported via the bloodstream to the liver where the message is translated, and the protein is synthesized by hepatocytes. Newly produced protein replaces the deficient or aberrant protein associated to the disease resulting in the rescue of metabolic function and fast reduction of toxic metabolite levels, consequently generating a therapeutic effect. Figure was created with biorender.com (accessed on 19 August 2022).