mRNA and gene editing: Late breaking therapies in liver diseases

Abstract

The efficient delivery of RNA molecules to restore the expression of a missing or inadequately functioning protein in a target cell and the intentional specific modification of the host genome using engineered nucleases represent therapeutic concepts that are revolutionizing modern medicine. The initiation of several clinical trials using these approaches to treat metabolic liver disorders as well as the recently reported remarkable results obtained by patients with transthyretin amyloidosis highlight the advances in this field and show the potential of these therapies to treat these diseases safely and efficaciously. These advances have been possible due, firstly, to significant improvements made in RNA chemistry that increase its stability and prevent activation of the innate immune response and, secondly, to the development of very efficient liver‐targeted RNA delivery systems. In parallel, the breakout of CRISPR/CRISPR‐associated 9–based technology in the gene editing field has marked a turning point in in vivo modification of the cellular genome with therapeutic purposes, which can be based on gene supplementation, correction, or silencing. In the coming years we are likely to witness the therapeutic potential of these two strategies both separately and in combination. In this review we summarize the preclinical data obtained in animal models treated with mRNA as a therapeutic agent and discuss the different gene editing strategies applied to the treatment of liver diseases, highlighting both their therapeutic efficacy as well as safety concerns.

mRNA-Based Approaches to Treating Liver Diseases

“…The potential efficacy of in vitro-transcribed mRNA used to treat liver diseases is based upon their ability to encode proteins that replace impaired hepatic functions using the translational machinery of the target cells, i.e., hepatocytes [ 17 ]. Therapeutic mRNA offers a distinct advantage over protein replacement or enzyme replacement therapy used to restore the functional proteins that are otherwise deficient or abnormal: mRNA delivered and expressed intracellularly allows post-translational modifications of the encoded protein by the host cells [ 18 ].…”

“…For most of these diseases, protein replacement is not an option; the only curative option is transplantation. Limitation in enzyme replacement includes the following: variability in a patient’s response, production of neutralizing antibodies, infusion reactions, and glycosylation pattern that affects the immunogenicity and/or function of the recombinant protein [ 17 ]. mRNA-based therapy offers an alternate approach.…”

“…The efficacy of mRNA-based protein replacement therapy utilizing systemic delivery of liver-targeting LNPs has been demonstrated in a number of animal models [ 12 , 17 ]. The following rare genetic disorders that affect the liver have been treated using mRNA in preclinical studies; a number have entered clinical trials.…”

Co-administration of an effector antibody enhances the half-life and therapeutic potential of RNA-encoded nanobodies

“…Besides vaccine applications, mRNA is being investigated for delivery of a wide variety of protein therapeutics. As examples, this strategy is showing promise for gene editing 30 , delivery of mAb products 31 , 32 and treating rare diseases with high medical need 33 – 36 .…”

How far are the new wave of mRNA drugs from us? mRNA product current perspective and future development

“…Pre-clinical human trials have been conducted for different therapies, and disease-specific mRNA vaccines and proven delivery systems have been developed, which may be developed on a large scale for disease prevention and treatment in the future ( Figure 3 ). mRNA therapies break through many of the limitations of traditional therapies and have the potential to become a novel therapeutic alternative to traditional treatments ( 39 , 40 ).…”