![]() The composition of the 3′ and 5′ UTRs can also be customized for the target cell of interest, increasing the efficiency and tissue specificity of translation 35, 38, 39.Īt present, most mRNA products contain a synthetic UTR sequence from α-globin or β-globin 38, 39, 40, but UTR optimization can further improve protein expression by a few fold 41, 42. Similarly, improved 5′ cap analogs not only increase translational capacity but also enhance capping efficiency, from 70% to 95%, greatly improving the in vitro transcription process 32, 37. Optimization of the poly(A) tail length (100–300 nucleotides) has proven critical in balancing the synthetic capability of a given mRNA 34, 36. 5′ cap analogs and 3′ poly(A) have been designed to maximize mRNA stability and translational efficiency through exonuclease protection and enhanced catalysis to the ribosomal complex 32, 33, 34, 35, 36. Finally, the sixth section considers the scope of mRNA therapeutics and guiding principles for near-term and longer-term clinical development of this novel therapeutic modality.Įach component of an individual mRNA-the cap, 5′ and 3′ untranslated regions (UTRs), open reading frame (ORF) and polyadenylated (poly(A)) tail-can be optimized to enhance protein expression (Fig. The fifth section provides a comprehensive table and summary of current clinical trends in mRNA therapeutics. The fourth section considers strategies for allowing repeated dosing for the treatment of chronic conditions. The third section discusses emerging approaches for targeting mRNA therapeutics to specific tissues, such as percutaneous catheters for delivery to the heart, pancreas and kidney, and the engineering of packaging systems with tissue-specific tropism. The second section explores improved mRNA packaging systems to enhance delivery of mRNA cargo, including ionizable LNPs, cells and cell-based extracellular vesicles. These approaches include advances in the design of the primary chemical structure of the mRNA, novel forms of circular and self-amplifying mRNA and improved purification strategies. The first section discusses approaches for designing and purifying the mRNA cargo to enhance the duration and amplitude of protein production in vivo. This review surveys the most promising of these new technologies. Despite these remaining challenges, a host of emerging technologies is under development to systematically address them 2, 7, 8, 9, 10, 11. Even with optimized mRNA chemical modifications and advanced LNPs, chronic dosing eventually activates innate immunity, with concomitant attenuation of therapeutic protein expression 5, 6. Another major hurdle is repeated dosing, which is often required in the treatment of chronic diseases. Aside from the liver, which is readily targeted by intravenous (i.v.) delivery, efficient delivery to solid organs remains challenging. The tissue bioavailability, circulatory half-life and efficiency of the lipid-based carrier to deliver to the tissue of interest can be strictly rate limiting. This requirement places greater importance on the efficiency of uptake at the target cell, which drives the duration and level of expression. In many cases, it will be necessary for mRNA therapeutics to engage a particular target pathway, cell, tissue or organ. In contrast, mRNA therapeutics require as much as a 1,000-fold-higher level of protein to reach a therapeutic threshold (Supplementary Table 1). Immunization requires only a minimal amount of protein production, as the immune system can markedly amplify the antigenic signal through cell-mediated and antibody-mediated immunity. The pathway for the development of mRNA therapeutics presents additional challenges compared to those of mRNA vaccines (Fig. The remarkably short timeframe from target identification to phase 1 clinical studies-and the convincing safety profile of mRNA vaccines after billions of administered doses-underscore the potential of a new generation of mRNA therapeutics that lies beyond vaccines and other agents that rely on the ability of mRNA and lipid nanoparticles (LNPs) to stimulate immune responses. ![]() The rapid design and development of two COVID-19 mRNA vaccines marked the advent of a new biotechnology platform for immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, potentially, a wide spectrum of microbial pathogens and cancers 1, 2, 3, 4.
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