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Mol Ther. 2019 Apr 10;27(4):824-836. doi: 10.1016/j.ymthe.2018.12.011. Epub 2018 Dec 18.

Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3' UTRs Identified by Cellular Library Screening.

Author information

1
Department for Internal Medicine, Johannes Gutenberg University, Mainz, Germany; BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
2
BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
3
BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
4
TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
5
Department for Internal Medicine, Johannes Gutenberg University, Mainz, Germany; BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany; TRON - Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. Electronic address: sahin@uni-mainz.de.

Abstract

Synthetic mRNA has emerged as a powerful tool for the transfer of genetic information, and it is being explored for a variety of therapeutic applications. Many of these applications require prolonged intracellular persistence of mRNA to improve bioavailability of the encoded protein. mRNA molecules are intrinsically unstable and their intracellular kinetics depend on the UTRs embracing the coding sequence, in particular the 3' UTR elements. We describe here a novel and generally applicable cell-based selection process for the identification of 3' UTRs that augment the expression of proteins encoded by synthetic mRNA. Moreover, we show, for two applications of mRNA therapeutics, namely, (1) the delivery of vaccine antigens in order to mount T cell immune responses and (2) the introduction of reprogramming factors into differentiated cells in order to induce pluripotency, that mRNAs tagged with the 3' UTR elements discovered in this study outperform those with commonly used 3' UTRs. This approach further leverages the utility of mRNA as a gene therapy drug format.

KEYWORDS:

3’ UTR library; RNA stability; cancer immunotherapy; cellular reprogramming; iPSCs; mRNA pharmacokinetics; mRNA therapeutics

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