Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of fu...

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Bibliographic Details
Published in:	Nature communications Vol. 11; no. 1; pp. 3501 - 13
Main Authors:	Lim, Kian Huat, Han, Zhou, Jeon, Hyun Yong, Kach, Jacob, Jing, Enxuan, Weyn-Vanhentenryck, Sebastien, Downs, Mikaela, Corrionero, Anna, Oh, Raymond, Scharner, Juergen, Venkatesh, Aditya, Ji, Sophina, Liau, Gene, Ticho, Barry, Nash, Huw, Aznarez, Isabel
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 09-07-2020 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 13/109 13/31 38/77 631/208/1792 631/61/391/1914 82/80 Alleles Alternative Splicing Animals Animals, Newborn Antisense oligonucleotides Bioinformatics Brain - metabolism Computational Biology Exons Female Gene expression Gene Expression - drug effects Gene Expression Regulation Gene sequencing HEK293 Cells Humanities and Social Sciences Humans Introns Male Mice Mice, Inbred C57BL Modulation multidisciplinary Oligonucleotides Oligonucleotides, Antisense - pharmacology Proteins Restoration RNA, Messenger - metabolism Science Science (multidisciplinary) Splicing Transcriptional Activation - drug effects Up-Regulation
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Summary:	While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of full-length protein by preventing naturally occurring non-productive alternative splicing and promoting generation of productive mRNA. Bioinformatics analysis of RNA sequencing data identifies non-productive splicing events in 7,757 protein-coding human genes, of which 1,246 are disease-associated. Antisense oligonucleotides targeting multiple types of non-productive splicing events lead to increases in productive mRNA and protein in a dose-dependent manner in vitro. Moreover, intracerebroventricular injection of two antisense oligonucleotides in wild-type mice leads to a dose-dependent increase in productive mRNA and protein in the brain. The targeting of natural non-productive alternative splicing to upregulate expression from wild-type or hypomorphic alleles provides a unique approach to treating genetic diseases. Restoration of normal gene expression is one way to treat monogenic disorders. Here the authors target naturally occurring non-productive alternative splicing using antisense oligonucleotides to promote the production of functional proteins.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-17093-9