Using modified mRNA for cardiomyocyte proliferation and cardiac genetic disease modelling and treatment.

Heart failure (HF) is a leading cause of death worldwide and the associated mortality and socioeconomic burden is predicted to worsen. Current therapies for HF focus on managing the causes and symptoms; however, these current treatment options are unable to reverse heart muscle degeneration, with heart transplantation the only cure. The ability to re-muscularise the heart represents a significant unmet clinical need. Although numerous biological pathways driving re-muscularisation have been identified, delivery of therapeutic factors is challenging. Modified mRNA (modRNA) is synthetic mRNA with greater gene packaging capacity, low immunogenic response and allows transient but robust protein expression. In this mini-review, we highlight the emerging discoveries surrounding the application of modRNA in the cardiovascular field. Specifically, we focus on different examples illustrating how modRNA delivery post-myocardial infarction can drive cardiomyocyte proliferation and achieve cardiac regeneration. In addition, we demonstrate how modRNA is being used for protein replacement and Cas delivery for both modelling and therapeutic studies focussed on genetic cardiac diseases. For these applications, in particular Cas delivery, the transient nature of modRNA overexpression is a beneficial property with reduced side effects compared with other modalities. Finally, we preview some of the roadblocks limiting the clinical translation of modRNA and avenues being explored to overcome these. In summary, the flexibility of modRNA combined with its improved safety profile provides a gene overexpression tool capable of integration into all steps of the preclinical and clinical therapeutic pipeline enabling the discovery of improved treatments for HF.