158. Chemically Modified Messenger RNA Furnished With Cellular UTRs Increases the Functional mRNA Productivity

Over the last decade, transcript therapy has emerged as a promising disease preventive and therapeutic approach. Messenger RNA successfully transfects slowly dividing primary cells without the risk of insertional mutagenesis. Hence, strategies like incorporation of chemically modified nucleotides within the mRNA and insertion of untranslated regions (UTRs) into the mRNA sequence, have been developed to increase stability and enhance translational efficiency of exogenous mRNA. The aim of the current project is to investigate a set of UTR sequences as “stability” and/or “translational enhancers”. To achieve this, various cellular UTRs were selected based on published mRNA stability and screened via different reporter assays both in immortalized cell lines and primary cells. We could observe longer expression with some of the tested UTR combinations compared to control mRNA without UTRs. Interestingly, the mRNA itself was neither stabilized nor differentially translated. Nonetheless, for some UTR containing constructs, higher protein expression normalized to the amount of delivered mRNA could be observed. The best working combination of UTRs is currently being incorporated into a vector coding for hBMP-2 and the resulting mRNAs would then be transfected in mesenchymal stem cells (rAMSCs) to induce osteogenic differentiation.