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REVIEWS
mRNA-based therapeutics developing a new class of drugs
Ugur Sahin1,2, Katalin Karik2,3 and zlem Treci1
Abstract | In vitro transcribed (IVT) mRNA has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Advances in addressing the inherent challenges of this drug class, particularly related to controlling the translational efficacy and immunogenicity of the IVTmRNA, provide the basis for a broad range of potential applications. mRNA-based cancer immunotherapies and infectious disease vaccines have entered clinical development. Meanwhile, emerging novel approaches include invivo delivery of IVT mRNA to replace or supplement proteins,
IVT mRNA-based generation of pluripotent stem cells and genome engineering using IVT mRNA-encoded designer nucleases. This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.
TRON Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany.
BioNTech Corporation, An der Goldgrube 12, 55131 Mainz, Germany.
Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. emails: mailto:[email protected]
Web End [email protected] ; mailto:[email protected]
Web End [email protected] ; mailto:[email protected]
Web End [email protected] doi:10.1038/nrd4278 Published online 19 September 2014
The concept of nucleic acid-encoded drugs was conceived over two decades ago when Wolff etal.1
demonstr ated that direct injection of in vitro transcribed (IVT) mRNA or plasmid DNA (pDNA) into the skeletal muscle of mice led to the expression of the encoded protein in the injected muscle. At the time, mRNA was not pursued further as it is less stable than DNA, and the field focused on technologies based on pDNA and viral DNA. Nevertheless, since its discovery in 1961, mRNA has been the subject of consistent basic and applied research for various diseases (FIG. 1(TIMELINE)). In the first decades after its discovery, the focus was on understanding the structural and functional aspects of mRNA and its metabolism in the eukaryotic cell. This is in addition to making tools for mRNA recombinant engineering more accessible to a broader research community. In the 1990s, preclinical exploration of IVT mRNA was initiated for diverse applications,...