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

Kian Huat Lim, Zhou Han, Hyun Yong Jeon, Jacob Kach, Enxuan Jing, Sebastien Weyn-Vanhentenryck, Mikaela Downs, Anna Corrionero, Raymond Oh, Juergen Scharner, Aditya Venkatesh, Sophina Ji, Gene Liau, Barry Ticho, Huw Nash and Isabel Aznarez ()
Additional contact information
Kian Huat Lim: Stoke Therapeutics, Inc.
Zhou Han: Stoke Therapeutics, Inc.
Hyun Yong Jeon: Stoke Therapeutics, Inc.
Jacob Kach: Stoke Therapeutics, Inc.
Enxuan Jing: Stoke Therapeutics, Inc.
Sebastien Weyn-Vanhentenryck: Stoke Therapeutics, Inc.
Mikaela Downs: Stoke Therapeutics, Inc.
Anna Corrionero: Stoke Therapeutics, Inc.
Raymond Oh: Stoke Therapeutics, Inc.
Juergen Scharner: Stoke Therapeutics, Inc.
Aditya Venkatesh: Stoke Therapeutics, Inc.
Sophina Ji: Stoke Therapeutics, Inc.
Gene Liau: Stoke Therapeutics, Inc.
Barry Ticho: Stoke Therapeutics, Inc.
Huw Nash: Stoke Therapeutics, Inc.
Isabel Aznarez: Stoke Therapeutics, Inc.

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-17093-9

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