My laboratory has studied RNA immunity for many years. We first identified that mRNA activated dendritic cells and was one of 3 groups that identified that TLR7 and TLR8 recognized RNA. We then went on to identify that the inclusion of modified nucleosides (pseudouridine, 5-Methyl-cytidine, and others) allowed the mRNA to avoid activation of RNA sensors. This allows mRNA delivered in vivo to give very high, up to 1,000-fold, more protein than unmodified mRNA. mRNA, unlike DNA, also has very high transfection efficiency in primary non-dividing cells. These properties allowed us to develop nucleoside-modified mRNA as a transient gene therapy to deliver or replace proteins as a therapeutic. We observed that 10 ng of erythropoietin encoding mRNA resulted in supraphysiologic responses in mice and 1 mg/kg of mAb encoding mRNAs resulted in circulating levels of mAb approaching 600 ug/ml. The combination of the extremely high potency of mRNA encoded proteins due to the amplification by translation and the reduced risks of adverse events as the protein is made by the host’s cells has made mRNA therapy a new approach to protein therapeutics. We have also used nucleoside-modified mRNA to deliver vaccine immunogens in many animal species including: mice, rats, Guinea pigs, rabbits, chickens, and Rhesus and Cynomolgus macaques resulting in potent antibody responses due to the specific induction of T follicular helper cells. This platform has been licensed by BioNTech and Moderna and is used in the first 2 COVID-19 vaccines that received EUA by the FDA. We have ongoing interests in developing many vaccines, including pan-coronavirus, hepatitis C, influenza, ebola, CMV, EBV, HIV, dengue, flaviviruses, and others that can quickly move into clinical trials. Additional studies have used modified mRNA for gene editing, as the kinetics of modified mRNA translation are ideal for the delivery of such systems and the targeting of mRNA-LNPs to specific cell types, including lung vascular endothelium, brain, cardiomyocytes, tissue T cells, and bone marrow stem cells.
