Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy

Kim, Young Jin, Nomakuchi, Tomoki, Papaleonidopoulou, Foteini, Yang, Lucia, Zhang, Qian, Krainer, Adrian R (May 2022) Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy. Nature Communications, 13 (1). p. 2978. ISSN 2041-1723

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Abstract

Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in developing a therapy for cystic fibrosis (CF) caused by the W1282X mutation in the CFTR gene. CFTR-W1282X truncated protein retains partial function, so increasing its levels by inhibiting NMD of its mRNA will likely be beneficial. Because NMD regulates the normal expression of many genes, gene-specific stabilization of CFTR-W1282X mRNA expression is more desirable than general NMD inhibition. Synthetic antisense oligonucleotides (ASOs) designed to prevent binding of exon junction complexes (EJC) downstream of premature termination codons (PTCs) attenuate NMD in a gene-specific manner. We describe cocktails of three ASOs that specifically increase the expression of CFTR-W1282X mRNA and CFTR protein upon delivery into human bronchial epithelial cells. This treatment increases the CFTR-mediated chloride current. These results set the stage for clinical development of an allele-specific therapy for CF caused by the W1282X mutation.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > congenital hereditary genetic diseases bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > congenital hereditary genetic diseases > cystic fibrosis bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > oligonucleotide
CSHL Authors:	Nomakuchi, Tomoki Yang, Lucia Zhang, Qian Krainer, Adrian R. Kim, Young Jin
Communities:	CSHL labs > Krainer lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	27 May 2022
Date Deposited:	02 Jun 2022 18:07
Last Modified:	09 Feb 2024 18:57
PMCID:	PMC9142507
URI:	https://repository.cshl.edu/id/eprint/40647

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