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Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames

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RNA Activation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 983))

Abstract

A number of diseases are caused by low levels of key proteins; therefore, increasing the amount of specific proteins in human bodies is of therapeutic interest. Protein expression is downregulated by some structural or sequence elements present in the 5′ UTR of mRNAs, such as upstream open reading frames (uORF). Translation initiation from uORF(s) reduces translation from the downstream primary ORF encoding the main protein product in the same mRNA, leading to a less efficient protein expression. Therefore, it is possible to use antisense oligonucleotides (ASOs) to specifically inhibit translation of the uORF by base-pairing with the uAUG region of the mRNA, redirecting translation machinery to initiate from the primary AUG site. Here we review the recent findings that translation of specific mRNAs can be enhanced using ASOs targeting uORF regions. Appropriately designed and optimized ASOs are highly specific, and they act in a sequence- and position-dependent manner, with very minor off-target effects. Protein levels can be increased using this approach in different types of human and mouse cells, and, importantly, also in mice. Since uORFs are present in around half of human mRNAs, the uORF-targeting ASOs may thus have valuable potential as research tools and as therapeutics to increase the levels of proteins for a variety of genes.

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Acknowledgments

This work has been supported by an internal funding from Ionis Pharmaceutics, Inc.

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  1. Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA

    Xue-Hai Liang, Wen Shen & Stanley T. Crooke

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  1. Xue-Hai Liang
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Correspondence to Xue-Hai Liang .

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  1. Laboratory of Molecular Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China

    Long-Cheng Li

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Liang, XH., Shen, W., Crooke, S.T. (2017). Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames. In: Li, LC. (eds) RNA Activation. Advances in Experimental Medicine and Biology, vol 983. Springer, Singapore. https://doi.org/10.1007/978-981-10-4310-9_9

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