Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Fr
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′
- PDF / 500,415 Bytes
- 18 Pages / 439.37 x 666.142 pts Page_size
- 95 Downloads / 187 Views
Specific Increase of Protein Levels by Enhancing Translation Using Antisense Oligonucleotides Targeting Upstream Open Frames Xue-Hai Liang, Wen Shen, and Stanley T. Crooke
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 50 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 sequenceand 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. Keywords Translation • uORF • Regulation • Antisense • Oligonucleotides
9.1
Introduction
Abnormal expression of proteins can cause diseases due to the essential roles that proteins play in various biological processes. Regulating protein expression or function is thus an important opportunity for therapeutics. Downregulation of
X.-H. Liang (*) • W. Shen • S.T. Crooke Department of Core Antisense Research, Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA 92010, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 L.-C. Li (ed.), RNA Activation, Advances in Experimental Medicine and Biology 983, DOI 10.1007/978-981-10-4310-9_9
129
130
X.-H. Liang et al.
specific protein expression via different mechanisms, especially using antisense technology, has been developed both as a research tool and for therapeutics [7, 14, 61, 77, 98]. The pharmacokinetics and pharmacodynamics of antisense oligonucleotide (ASO) drugs have been well studied and efficient delivery of ASOs in vivo to different organs has been achieved via many different routes, including subcutaneous injection [24–26, 38]. Importantly, ASO drugs have been approved by FDA, for example, for the treatment of patients with homozygous familial hypercholesterolemia [90]. However, in many cases a disease can be caused by low levels of functional proteins [16, 79]; therefore, specific increases in the amount of a protein may be beneficial. Multiple approaches have been developed to achieve this purpose, such as delivery
Data Loading...
