Delivering the Message: Translating mRNA Therapy for Liver Inherited Metabolic Diseases

Abstract

mRNA encapsulated in lipid nanoparticles (LNPs) provides a dual revolution in the field of gene therapy. mRNA brings fleeting efficacy and the possibility to adjust the therapy to clinical needs. LNP, as a non-viral vehicle with flexible organ-targeting, overcomes most immune complications of viral gene therapy. mRNA-LNP has rapidly progressed from preventive medicine and vaccine applications to therapeutic use, especially in inherited metabolic diseases (IMDs). Given their natural tropism for liver uptake, this platform has been utilised successfully in numerous preclinical programmes. Early phase clinical trials are recruiting to assess safety and efficacy in liver IMDs. Here, we provide the latest update on mRNA and LNP technologies, preclinical studies and clinical trials targeting IMDs, safety considerations with a spotlight on infusion-related reactions and safety modelling. We discuss the future directions of therapeutic mRNA-LNP in IMDs and the right clinical use of this adjustable therapy, still to be defined. The versatility of this technology is appealing, with multiple clinical applications as bridge, long-term cure, rescue, or adjuvant therapy. mRNA-LNP for gene editing/insertion is an alternative approach for one-off cure. Translating various successful preclinical programmes in patients remains an unsolved limitation. mRNA-LNP can be tuned according to the patient's needs and is the next step in personalised medicine and individualised gene therapy.