Antisense oligonucleotides targeting translation inhibitory elements in 5' UTRs can selectively increase protein levels.

Autor:	Liang XH; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Sun H; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Shen W; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Wang S; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Yao J; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Migawa MT; Department of Medicinal Chemistry, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Bui HH; Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Damle SS; Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Riney S; Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Graham MJ; Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Crooke RM; Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA., Crooke ST; Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2017 Sep 19; Vol. 45 (16), pp. 9528-9546.
DOI:	10.1093/nar/gkx632
Abstrakt:	A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5' UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5' UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5' UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials. (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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